rs148713761

chr17-37733709-G-Achr17-37733709-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000458.4(HNF1B):c.657C>T(p.Ser219=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 mid. gnomad4_exome allele frequency = 0.000194 (283/1461892) while in subpopulation MID AF= 0.00173 (10/5768). AF 95% confidence interval is 0.00094. There are 1 homozygotes in gnomad4_exome. There are 138 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.657C>T	p.Ser219=	synonymous_variant	3/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.657C>T	p.Ser219=	synonymous_variant	3/9	1	NM_000458.4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152108 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000306 AC: 77 AN: 251466 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135910

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 SAS exome AF: 0.0000653

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.: 1 Cov.: 33 AF XY: 0.000190 AC XY: 138 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00375

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74416

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000513 Hom.: 0

Bravo AF: 0.000212

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 12, 2023	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	HNF1B: BP4, BP7 -

Maturity onset diabetes mellitus in young Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 24, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	HNF1B gene mutations are associated with early onset diabetes and pancreatic atrophy. It is also associated with multiple renal manifestations including renal cysts, Tubulointerstitial disease, glomerulocystic disease, renal hypoplasia, hypomagnesemia.However no sufficient evidence is found to ascertain the role of this particular variant rs148713761, yet. -

Renal cysts and diabetes syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	13
Dann	Benign	0.74

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

LitVar

Other links and lift over

dbSNP: rs148713761; hg19: chr17-36093702;