rs4239217

Variant names:

• chr17-37738996-A-G
• rs4239217
• NM_000458.4:c.544+444T>C

Variant summary

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

The NM_000458.4(HNF1B):​c.544+444T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 152,118 control chromosomes in the GnomAD database, including 9,475 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 0.35 (9475 hom., cov: 32)
• Consequence: HNF1B NM_000458.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.450
• Publications: 28 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.544+444T>C		intron_variant	Intron 2 of 8	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5	c.544+444T>C		intron_variant	Intron 2 of 8	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.544+444T>C		intron_variant	Intron 2 of 8	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.544+444T>C		intron_variant	Intron 2 of 6	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.544+444T>C		intron_variant	Intron 2 of 7	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52975 AN: 152000 Hom.: 9475 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.359

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

GnomAD4 genome AF: 0.348 AC: 52974 AN: 152118 Hom.: 9475 Cov.: 32 AF XY: 0.343 AC XY: 25524 AN XY: 74364

African (AFR) AF: 0.295 AC: 12233 AN: 41482

American (AMR) AF: 0.345 AC: 5274 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1470 AN: 3472

East Asian (EAS) AF: 0.295 AC: 1523 AN: 5170

South Asian (SAS) AF: 0.311 AC: 1497 AN: 4812

European-Finnish (FIN) AF: 0.283 AC: 2995 AN: 10594

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26730 AN: 67984

Other (OTH) AF: 0.354 AC: 748 AN: 2114

Alfa AF: 0.381 Hom.: 10745

Bravo AF: 0.350

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.0
PhyloP100		-0.45

Splicing

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

Other links and lift over

dbSNP: rs4239217; hg19: chr17-36098987;