rs1058166

chr17-37686988-T-C

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.*384A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 461,494 control chromosomes in the GnomAD database, including 5,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4424 hom., cov: 32)
  • Exomes 𝑓: 0.068 (1522 hom.)
• Consequence: HNF1B NM_000458.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0240

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=-0.48).
• BP6: Variant 17-37686988-T-C is Benign according to our data. Variant chr17-37686988-T-C is described in ClinVar as [Benign]. Clinvar id is 322938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1B	NM_000458.4	c.*384A>G		3_prime_UTR_variant	9/9	ENST00000617811.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1B	ENST00000617811.5	c.*384A>G		3_prime_UTR_variant	9/9	1	NM_000458.4

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25629 AN: 152070 Hom.: 4411 Cov.: 32

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.0620

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.0680 AC: 21029 AN: 309306 Hom.: 1522 Cov.: 0 AF XY: 0.0655 AC XY: 10712 AN XY: 163458

Gnomad4 AFR exome AF: 0.440

Gnomad4 AMR exome AF: 0.0716

Gnomad4 ASJ exome AF: 0.0648

Gnomad4 EAS exome AF: 0.0000535

Gnomad4 SAS exome AF: 0.0460

Gnomad4 FIN exome AF: 0.0502

Gnomad4 NFE exome AF: 0.0602

Gnomad4 OTH exome AF: 0.0891

GnomAD4 genome AF: 0.169 AC: 25687 AN: 152188 Hom.: 4424 Cov.: 32 AF XY: 0.165 AC XY: 12296 AN XY: 74412

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.0902

Gnomad4 ASJ AF: 0.0700

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0381

Gnomad4 FIN AF: 0.0623

Gnomad4 NFE AF: 0.0620

Gnomad4 OTH AF: 0.155

Alfa AF: 0.0827 Hom.: 1559

Bravo AF: 0.184

Asia WGS AF: 0.0590 AC: 206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 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 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. -

Maturity onset diabetes mellitus in young Benign:1

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 rs1058166, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.2
Dann	Benign	0.68

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: rs1058166; hg19: chr17-36046991;