rs3094509

Variant names:

• chr17-37702294-G-A
• rs3094509
• NM_000458.4:c.1340-1117C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000458.4(HNF1B):​c.1340-1117C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 151,954 control chromosomes in the GnomAD database, including 18,526 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (18526 hom., cov: 31)
• Consequence: HNF1B NM_000458.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.625
• Publications: 11 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.1340-1117C>T		intron_variant	Intron 6 of 8	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5	c.1340-1117C>T		intron_variant	Intron 6 of 8	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.1262-1117C>T		intron_variant	Intron 6 of 8	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.1261+2623C>T		intron_variant	Intron 6 of 6	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.1340-1117C>T		intron_variant	Intron 6 of 7	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71648 AN: 151836 Hom.: 18498 Cov.: 31

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.460

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.472 AC: 71711 AN: 151954 Hom.: 18526 Cov.: 31 AF XY: 0.473 AC XY: 35086 AN XY: 74240

African (AFR) AF: 0.701 AC: 29039 AN: 41416

American (AMR) AF: 0.368 AC: 5624 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1561 AN: 3470

East Asian (EAS) AF: 0.462 AC: 2387 AN: 5166

South Asian (SAS) AF: 0.474 AC: 2277 AN: 4808

European-Finnish (FIN) AF: 0.398 AC: 4206 AN: 10564

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25065 AN: 67944

Other (OTH) AF: 0.455 AC: 960 AN: 2108

Alfa AF: 0.412 Hom.: 7274

Bravo AF: 0.479

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.2
PhyloP100		0.63

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3094509; hg19: chr17-36062299;