chr17-37687389-G-T

Position:

chr17-37687389-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000458.4(HNF1B):c.1657C>A(p.Pro553Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000292 in 1,612,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

HNF1B
NM_000458.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 6.24

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1B	NM_000458.4 linkuse as main transcript	c.1657C>A	p.Pro553Thr	missense_variant	9/9	ENST00000617811.5	NP_000449.1	P35680-1Q6FHW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HNF1B	ENST00000617811.5 linkuse as main transcript	c.1657C>A	p.Pro553Thr	missense_variant	9/9	1	NM_000458.4	ENSP00000480291.1	P35680-1
HNF1B	ENST00000621123.4 linkuse as main transcript	c.1579C>A	p.Pro527Thr	missense_variant	9/9	1		ENSP00000482711.1	P35680-2
HNF1B	ENST00000613727.4 linkuse as main transcript	c.1265C>A	p.Ser422Tyr	missense_variant	7/7	1		ENSP00000477524.1	A0A0C4DGS8
HNF1B	ENST00000614313.4 linkuse as main transcript	c.1538C>A	p.Ser513Tyr	missense_variant	8/8	5		ENSP00000482529.1	A0A087WZC2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251166

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1459978

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726426

show subpopulations

Gnomad4 AFR exome

AF:

0.000658

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000158

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000579

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000215

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2022	Reported in a patient with diabetes in published literature (Dubois-Laforgue et al., 2017); clinical information was not provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28420700) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 553 of the HNF1B protein (p.Pro553Thr). This variant is present in population databases (rs147798914, gnomAD 0.03%). This missense change has been observed in individual(s) with HNF1B-related conditions (PMID: 28420700). ClinVar contains an entry for this variant (Variation ID: 499802). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

HNF1B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2024

The HNF1B c.1657C>A variant is predicted to result in the amino acid substitution p.Pro553Thr. This variant was reported in an individual with diabetes, but the clinical significance was uncertain (Table S1, Dubois-Laforgue et al. 2017. PubMed ID: 28420700). This variant is reported in 0.032% 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

Uncertain significance, criteria provided, single submitter

literature only

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

Jul 06, 2019

- -

Maturity onset diabetes mellitus in young

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.1657C>A (p.P553T) alteration is located in exon 9 (coding exon 9) of the HNF1B gene. This alteration results from a C to A substitution at nucleotide position 1657, causing the proline (P) at amino acid position 553 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (8/282558) total alleles studied. The highest observed frequency was 0.032% (8/24962) of African alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Benign

0.80

DEOGEN2

Uncertain

0.48

T;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

0.54

PrimateAI

Uncertain

0.76

Sift4G

Uncertain

0.040

D;D

Polyphen

0.058

B;.

Vest4

0.71

MVP

0.76

ClinPred

0.71

GERP RS

5.8

Varity_R

0.44

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over