rs144425830

Variant names:

• chr17-37744659-C-A
• rs144425830
• NM_000458.4:c.226G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 4P and 11B. PM1 PP2 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:4 B:11
• 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

Our verdict: Benign. The variant received -7 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, 6 uncertain in NM_000458.4
• 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: 2.0703 (below the threshold of 3.09). GenCC associations: The gene is linked to medullary sponge kidney, renal dysplasia, unilateral, renal hypomagnesemia 2, transient neonatal diabetes mellitus, renal dysplasia, bilateral, renal cysts and diabetes syndrome, unilateral multicystic dysplastic kidney, diabetes mellitus, noninsulin-dependent, permanent neonatal diabetes mellitus.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PrimateAI, REVEL [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: {Uncertain_significance=4, Likely_benign=6, Benign=1}. 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 the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.226G>T	p.Gly76Cys	missense_variant	Exon 1 of 9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5	c.226G>T	p.Gly76Cys	missense_variant	Exon 1 of 9	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.226G>T	p.Gly76Cys	missense_variant	Exon 1 of 9	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.226G>T	p.Gly76Cys	missense_variant	Exon 1 of 7	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.226G>T	p.Gly76Cys	missense_variant	Exon 1 of 8	5		ENSP00000482529.1

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

GnomAD2 exomes AF: 0.000575 AC: 144 AN: 250430 AF XY: 0.000634

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 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 AC: 10 AN: 33478

Gnomad4 AMR exome AF: 0.00208 AC: 93 AN: 44716

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26126

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.0000580 AC: 5 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52388

Gnomad4 NFE exome AF: 0.000328 AC: 365 AN: 1111988

Gnomad4 Remaining exome AF: 0.00106 AC: 64 AN: 60390

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 AC: 0.000408673 AN: 0.000408673

Gnomad4 AMR AF: 0.00274 AC: 0.00274402 AN: 0.00274402

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000941 AC: 0.0000940734 AN: 0.0000940734

Gnomad4 NFE AF: 0.000367 AC: 0.000367463 AN: 0.000367463

Gnomad4 OTH AF: 0.00189 AC: 0.00189036 AN: 0.00189036

Alfa AF: 0.000422 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:4 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2018

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Nov 15, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3 -

Renal cysts and diabetes syndrome Uncertain:2 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 06, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Jun 04, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

HNF1B-related disorder Benign:1

Jan 29, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital anomaly of kidney and urinary tract Benign:1

Oct 25, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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;.;.;.;.
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
Mutation Taster		=24/76	disease causing

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;