dbSNP rs148713761: HNF1B:p.Ser219Ser (chr17-37733709-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000458.4(HNF1B):c.657C>T(p.Ser219Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S219S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

HNF1B
NM_000458.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.96

Publications

3 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, ClinGen
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 17-37733709-G-A is Benign according to our data. Variant chr17-37733709-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 511470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.96 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000184 (28/152226) while in subpopulation AMR AF = 0.000196 (3/15296). AF 95% confidence interval is 0.000112. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000458.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1B	NM_000458.4	MANE Select	c.657C>T	p.Ser219Ser	synonymous	Exon 3 of 9	NP_000449.1	P35680-1
HNF1B	NM_001411100.1		c.657C>T	p.Ser219Ser	synonymous	Exon 3 of 8	NP_001398029.1	A0A087WZC2
HNF1B	NM_001165923.4		c.579C>T	p.Ser193Ser	synonymous	Exon 3 of 9	NP_001159395.1	E0YMJ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNF1B	ENST00000617811.5	TSL:1 MANE Select	c.657C>T	p.Ser219Ser	synonymous	Exon 3 of 9	ENSP00000480291.1	P35680-1
HNF1B	ENST00000621123.4	TSL:1	c.579C>T	p.Ser193Ser	synonymous	Exon 3 of 9	ENSP00000482711.1	P35680-2
HNF1B	ENST00000613727.4	TSL:1	c.579C>T	p.Ser193Ser	synonymous	Exon 3 of 7	ENSP00000477524.1	A0A0C4DGS8

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000306

AC:

AN:

251466

AF XY:

0.000265

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000194

AC:

283

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

138

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000127

AC:

141

AN:

1112010

Other (OTH)

AF:

0.000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000184

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41522

American (AMR)

AF:

0.000196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000513

Hom.:

Bravo

AF:

0.000212

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Maturity-onset diabetes of the young (2)

Renal cysts and diabetes syndrome (1)

Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome;CN074294:Nonpapillary renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over