NM_000458.4:c.*99C>A

Variant names:

• chr17-37687273-G-T
• rs2229295
• NM_000458.4:c.*99C>A

Variant summary

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

The NM_000458.4(HNF1B):​c.*99C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,603,650 control chromosomes in the GnomAD database, including 32,572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6842 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25730 hom.)
• Consequence: HNF1B NM_000458.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.447

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 (BayesDel_noAF=-0.71).
• BP6: Variant 17-37687273-G-T is Benign according to our data. Variant chr17-37687273-G-T is described in ClinVar as [Benign]. Clinvar id is 322941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-37687273-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.*99C>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811	c.*99C>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123	c.*99C>A		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000482711.1
HNF1B	ENST00000613727	c.*7C>A		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000477524.1
HNF1B	ENST00000614313	c.*7C>A		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39916 AN: 151942 Hom.: 6817 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.258

GnomAD3 exomes AF: 0.190 AC: 47177 AN: 248192 Hom.: 5605 AF XY: 0.188 AC XY: 25185 AN XY: 134166

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.179 AC: 259225 AN: 1451592 Hom.: 25730 Cov.: 30 AF XY: 0.180 AC XY: 129772 AN XY: 722564

Gnomad4 AFR exome AF: 0.511

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.226

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.263 AC: 39998 AN: 152058 Hom.: 6842 Cov.: 32 AF XY: 0.260 AC XY: 19348 AN XY: 74324

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.230

Gnomad4 EAS AF: 0.0987

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.260

Alfa AF: 0.212 Hom.: 971

Bravo AF: 0.276

Asia WGS AF: 0.186 AC: 649 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26329304) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Renal cysts and diabetes syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.8
DANN	Benign	0.82

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: rs2229295; hg19: chr17-36047276;