rs1058166

Variant names:

• chr17-37686988-T-C
• rs1058166
• NM_000458.4:c.*384A>G

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.0240
• Publications: 12 publications found

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]

HNF1B Gene-Disease associations (from GenCC):

• renal cysts and diabetes syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• medullary sponge kidney

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal dysplasia, bilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal dysplasia, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal hypomagnesemia 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• unilateral multicystic dysplastic kidney

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000277688 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.*384A>G		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	ENST00000617811.5	c.*384A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_000458.4	ENSP00000480291.1

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

African (AFR) AF: 0.440 AC: 4048 AN: 9208

American (AMR) AF: 0.0716 AC: 1024 AN: 14304

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 596 AN: 9200

East Asian (EAS) AF: 0.0000535 AC: 1 AN: 18680

South Asian (SAS) AF: 0.0460 AC: 1886 AN: 40966

European-Finnish (FIN) AF: 0.0502 AC: 822 AN: 16360

Middle Eastern (MID) AF: 0.112 AC: 144 AN: 1290

European-Non Finnish (NFE) AF: 0.0602 AC: 10957 AN: 181884

Other (OTH) AF: 0.0891 AC: 1551 AN: 17414

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

African (AFR) AF: 0.446 AC: 18487 AN: 41476

American (AMR) AF: 0.0902 AC: 1380 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5178

South Asian (SAS) AF: 0.0381 AC: 184 AN: 4826

European-Finnish (FIN) AF: 0.0623 AC: 661 AN: 10612

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.0620 AC: 4218 AN: 68020

Other (OTH) AF: 0.155 AC: 326 AN: 2108

Alfa AF: 0.109 Hom.: 4614

Bravo AF: 0.184

Asia WGS AF: 0.0590 AC: 206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

Maturity onset diabetes mellitus in young Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.2
DANN	Benign	0.68
PhyloP100		-0.024
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1058166; hg19: chr17-36046991;