rs8068014

chr17-37687325-A-Cchr17-37687325-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000613727.4(HNF1B):c.1329T>G(p.Phe443Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00501 in 1,614,022 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (177 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (195 hom.)
• Consequence: HNF1B ENST00000613727.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.69

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018926263).
• BP6: Variant 17-37687325-A-C is Benign according to our data. Variant chr17-37687325-A-C is described in ClinVar as [Benign]. Clinvar id is 322943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.092 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.*47T>G		3_prime_UTR_variant	9/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000613727.4	c.1329T>G	p.Phe443Leu	missense_variant	7/7	1
HNF1B	ENST00000617811.5	c.*47T>G		3_prime_UTR_variant	9/9	1	NM_000458.4
HNF1B	ENST00000621123.4	c.*47T>G		3_prime_UTR_variant	9/9	1		P1
HNF1B	ENST00000614313.4	c.1602T>G	p.Phe534Leu	missense_variant	8/8	5

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4090 AN: 152142 Hom.: 177 Cov.: 32

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00705 AC: 1773 AN: 251314 Hom.: 75 AF XY: 0.00518 AC XY: 704 AN XY: 135824

Gnomad AFR exome AF: 0.0977

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00273 AC: 3988 AN: 1461762 Hom.: 195 Cov.: 32 AF XY: 0.00242 AC XY: 1761 AN XY: 727172

Gnomad4 AFR exome AF: 0.0988

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00498

GnomAD4 genome AF: 0.0269 AC: 4092 AN: 152260 Hom.: 177 Cov.: 32 AF XY: 0.0257 AC XY: 1915 AN XY: 74452

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0132 Hom.: 23

Bravo AF: 0.0298

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0919 AC: 405

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00872 AC: 1059

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cysts and diabetes syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Oct 11, 2016

ACMG Criteria: PP3, BS1 (ExAC AFR), BS2 (ExAC, type2diabetesgenetics.org), BP4 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	14
Dann	Uncertain	1.0
DEOGEN2	Benign	0.083	T;T
Eigen	Benign	0.10
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0019	T;T
MetaSVM	Uncertain	-0.097	T
MutationTaster	Benign	1.0	D;D;N;N
Sift4G	Benign	0.64	T;T
Vest4		0.25
MVP		0.76
ClinPred		0.015	T
GERP RS		4.9

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: rs8068014; hg19: chr17-36047328;