17-37686747-G-A

Position:

• chr17-37686747-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000458.4(HNF1B):​c.*625C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 177,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: HNF1B NM_000458.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.400

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 17-37686747-G-A is Benign according to our data. Variant chr17-37686747-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 892035.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00146 (223/152268) while in subpopulation NFE AF= 0.00229 (156/68018). AF 95% confidence interval is 0.002. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 223 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.*625C>T		3_prime_UTR_variant	9/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.*625C>T		3_prime_UTR_variant	9/9	1	NM_000458.4

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00336

GnomAD4 exome AF: 0.00204 AC: 52 AN: 25436 Hom.: 0 Cov.: 0 AF XY: 0.00198 AC XY: 27 AN XY: 13608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000534

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00267

Gnomad4 OTH exome AF: 0.00651

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74452

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00173

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Renal cysts and diabetes syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

HNF1B gene mutations are associated with early onset diabetes and pancreatic atrophy. It is also associated with multiple renal manifestations including renal cysts, Tubulointerstitial disease, glomerulocystic disease, renal hypoplasia, hypomagnesemia. However no sufficient evidence is found to ascertain the role of this particular variant rs188957129, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.4
DANN	Benign	0.83

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: rs188957129; hg19: chr17-36046750;