rs144425830

Positions:

• chr17-37744659-C-A
• chr17-37744659-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 3P and 11B. PM1 PP3 BP4_Moderate BP6 BS1 BS2

The NM_000458.4(HNF1B):​c.226G>T​(p.Gly76Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,613,178 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 0.00062 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: HNF1B NM_000458.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 7.68

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 -8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000458.4
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PrimateAI [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.15736353).
• BP6: Variant 17-37744659-C-A is Benign according to our data. Variant chr17-37744659-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193102.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3}. Variant chr17-37744659-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000623 (95/152370) while in subpopulation AMR AF= 0.00274 (42/15306). AF 95% confidence interval is 0.00209. There are 1 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.226G>T	p.Gly76Cys	missense_variant	1/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.226G>T	p.Gly76Cys	missense_variant	1/9	1	NM_000458.4
HNF1B	ENST00000621123.4	c.226G>T	p.Gly76Cys	missense_variant	1/9	1		P1
HNF1B	ENST00000613727.4	c.226G>T	p.Gly76Cys	missense_variant	1/7	1
HNF1B	ENST00000614313.4	c.226G>T	p.Gly76Cys	missense_variant	1/8	5

Frequencies

GnomAD3 genomes AF: 0.000617 AC: 94 AN: 152252 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000575 AC: 144 AN: 250430 Hom.: 1 AF XY: 0.000634 AC XY: 86 AN XY: 135656

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000375 AC: 548 AN: 1460808 Hom.: 2 Cov.: 35 AF XY: 0.000359 AC XY: 261 AN XY: 726774

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000328

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000623 AC: 95 AN: 152370 Hom.: 1 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74516

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000846

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000763

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2022	Identified in multiple patients with structural renal abnormalities, however, family segregation studies have been limited, functional studies have not been performed, and only the HNF1B gene was sequenced in most publications (Ulinski et al., 2006; Nakayama et al., 2010; Musetti et al., 2014, Raaijmakers et al., 2015; Okorn et al., 2019); Identified in an individual with maturity-onset diabetes of the young, however, additional clinical and segregation information was not provided (Bellanne-Chatelot et al., 2005); Identified in randomly selected individuals from the Framingham and Jackson Heart Studies (Flannick et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21775974, 24097065, 24387224, 20155289, 26764160, 25500806, 16249435, 30666461, 16371430, 31365591, 34426522, 33324081) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 23, 2018	- -

Renal cysts and diabetes syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	literature only	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Jul 06, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Renal cysts and diabetes syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder (PMID:23539225). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 04, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2023	- -

HNF1B-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nonpapillary renal cell carcinoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Congenital anomaly of kidney and urinary tract Benign:1

Likely benign, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Oct 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;T;T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.58
MVP		0.98
ClinPred		0.061	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		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: rs144425830; hg19: chr17-36104650;