chr17-37710601-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000458.4(HNF1B):c.1108G>A(p.Gly370Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,076 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

HNF1B
NM_000458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 4.53

Publications

4 publications found

Variant links:

Genes affected

HNF1B (HGNC:11630): (HNF1 homeobox B) This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

HNF1B Gene-Disease associations (from GenCC):

renal cysts and diabetes syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
diabetes mellitus, noninsulin-dependent
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
permanent neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
transient neonatal diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
medullary sponge kidney
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal dysplasia, bilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal dysplasia, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal hypomagnesemia 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
unilateral multicystic dysplastic kidney
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNF1B links:

ENSG00000302846 (HGNC:):

ENSG00000302846 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 72 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: 2.0703 (below the threshold of 3.09). GenCC associations: The gene is linked to unilateral multicystic dysplastic kidney, renal dysplasia, unilateral, renal cysts and diabetes syndrome, medullary sponge kidney, renal hypomagnesemia 2, renal dysplasia, bilateral, diabetes mellitus, noninsulin-dependent, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus.

BP4

Computational evidence support a benign effect (MetaRNN=0.06089571).

BP6

Variant 17-37710601-C-T is Benign according to our data. Variant chr17-37710601-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379811.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000447 (68/152270) while in subpopulation AFR AF = 0.00159 (66/41554). AF 95% confidence interval is 0.00128. There are 1 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4 link	c.1108G>A	p.Gly370Ser	missense_variant	Exon 5 of 9	ENST00000617811.5	NP_000449.1	P35680-1Q6FHW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5 link	c.1108G>A	p.Gly370Ser	missense_variant	Exon 5 of 9	1	NM_000458.4	ENSP00000480291.1		P35680-1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000135

AC:

AN:

251104

AF XY:

0.0000958

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00299

AC:

100

AN:

33474

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112000

Other (OTH)

AF:

0.000894

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000447

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41554

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.000563

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Jun 28, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in patients with MODY or renal cysts and diabetes syndrome; however, additional information is not available (Bellanne-Chantelot et al., 2005; Poitou et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22432796, 28453780, 21163139, 25700310, 27535533, 16249435, 24097065, 32041611) -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BS2 -

HNF1B-related disorder

Uncertain:1

Jan 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HNF1B c.1108G>A variant is predicted to result in the amino acid substitution p.Gly370Ser. This variant has been reported in individuals with maturity-onset diabetes of the young type 5, also referred to as renal cysts and diabetes syndrome (Bellanne-Chantelot et al. 2005. PubMed ID: 16249435; referred to as rs113042313, Elashi et al. 2022. PubMed ID: 36613572). It has also been reported an individual without diabetes (Supplementary Tables 2 and 3, Flannick et al. 2013. PubMed ID: 24097065). No family or functional studies were performed to help assess its pathogenicity. This variant is reported in 0.18% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Renal cysts and diabetes syndrome

Uncertain:1

Jul 06, 2019

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome

Uncertain:1

Nov 30, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The heterozygous c.1108G>A (p.Gly370Ser) missense variant identified in HNF1B has been previously reported in association with maturity-onset diabetes of the young type 5/ renal cysts and diabetes syndrome [PMID: 16249435;PMID: 2243279;PMID: 24097065]. Functional studies to evaluate the potential pathogenicity of this variant were not performed. This variant has been reported as a variant of uncertain in the ClinVar database [Variation ID:379811]. The variant has 0.001521 allele frequency in the African/African-American subpopulation of the gnomAD(v3) database (63 out of 41,432 heterozygous alleles, 1 homozygous allele). The affected Gly370 residue is not highly conserved and in silico tools provide conflicting interpretations about potential pathogenicity of this variant. Based on the available evidence, the c.1108G>A (p.Gly370Ser) missense variant in the HNF1B gene is reported as a variant of uncertain significance. -

Maturity onset diabetes mellitus in young

Uncertain:1

Oct 30, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G370S variant (also known as c.1108G>A), located in coding exon 5 of the HNF1B gene, results from a G to A substitution at nucleotide position 1108. The glycine at codon 370 is replaced by serine, an amino acid with similar properties. This variant was detected in a cohort of individuals with maturity-onset diabetes of young(MODY)/renal cysts and diabetes (RCAD) (Bellanné-Chantelot C et al. Diabetes, 2005 Nov;54:3126-32; Poitou C et al. Transpl. Int., 2012 May;25:564-72). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Aug 17, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.50

D;.;T;T;.

Eigen

Benign

-0.089

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.86

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.061

T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;.;.;.;.

PhyloP100

4.5

PrimateAI

Uncertain

0.49

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.23

B;.;.;.;.

Vest4

0.50

MVP

0.76

ClinPred

0.029

GERP RS

5.7

Varity_R

0.54

gMVP

0.50

Mutation Taster

=35/65

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over