Genetic Variant HNF1B:p.Phe443Leu (chr17-37687325-A-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000613727.4(HNF1B):c.1329T>G(p.Phe443Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00501 in 1,614,022 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 177 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 195 hom. )

Consequence

HNF1B
ENST00000613727.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.69

Publications

12 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:

ENSG00000277688 (HGNC:):

ENSG00000277688 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 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: 2.0663 (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=0.0018926263).

BP6

Variant 17-37687325-A-C is Benign according to our data. Variant chr17-37687325-A-C is described in ClinVar as Benign. ClinVar VariationId is 322943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.092 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000613727.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HNF1B	NM_000458.4	MANE Select	c.*47T>G		3_prime_UTR	Exon 9 of 9	NP_000449.1
HNF1B	NM_001411100.1		c.1602T>G	p.Phe534Leu	missense	Exon 8 of 8	NP_001398029.1
HNF1B	NM_001304286.2		c.1329T>G	p.Phe443Leu	missense	Exon 7 of 7	NP_001291215.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HNF1B	ENST00000613727.4	TSL:1	c.1329T>G	p.Phe443Leu	missense	Exon 7 of 7	ENSP00000477524.1
HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.*47T>G		3_prime_UTR	Exon 9 of 9	ENSP00000480291.1
HNF1B	ENST00000621123.4	TSL:1	c.*47T>G		3_prime_UTR	Exon 9 of 9	ENSP00000482711.1

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

4090

AN:

152142

Hom.:

177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0946

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.00705

AC:

1773

AN:

251314

AF XY:

0.00518

show subpopulations

Gnomad AFR exome

AF:

0.0977

Gnomad AMR exome

AF:

0.00405

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00273

AC:

3988

AN:

1461762

Hom.:

195

Cov.:

AF XY:

0.00242

AC XY:

1761

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0988

AC:

3308

AN:

33476

American (AMR)

AF:

0.00474

AC:

212

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000185

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000127

AC:

141

AN:

1111998

Other (OTH)

AF:

0.00498

AC:

301

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

231

462

693

924

1155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.0269

AC:

4092

AN:

152260

Hom.:

177

Cov.:

AF XY:

0.0257

AC XY:

1915

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0944

AC:

3921

AN:

41524

American (AMR)

AF:

0.00713

AC:

109

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68016

Other (OTH)

AF:

0.0189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

193

387

580

774

967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0279

Hom.:

112

Bravo

AF:

0.0298

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0919

AC:

405

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00872

AC:

1059

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jul 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Renal cysts and diabetes syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Monogenic diabetes

Benign:1

Oct 11, 2016

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria: PP3, BS1 (ExAC AFR), BS2 (ExAC, type2diabetesgenetics.org), BP4

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

Eigen

Benign

0.10

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.0019

MetaSVM

Uncertain

-0.097

PhyloP100

2.7

Sift4G

Benign

0.64

Vest4

0.25

MVP

0.76

ClinPred

0.015

GERP RS

4.9

Mutation Taster

=85/15

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over