17-37738049-A-G

Variant names:

• chr17-37738049-A-G
• rs4430796
• NM_000458.4:c.544+1391T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000458.4(HNF1B):​c.544+1391T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 151,996 control chromosomes in the GnomAD database, including 20,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.51 (20898 hom., cov: 32)
• Consequence: HNF1B NM_000458.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.110
• Publications: 399 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-37738049-A-G is Benign according to our data. Variant chr17-37738049-A-G is described in ClinVar as Benign. ClinVar VariationId is 1687622.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.544+1391T>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+1391T>C		intron_variant	Intron 2 of 8	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.544+1391T>C		intron_variant	Intron 2 of 8	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.544+1391T>C		intron_variant	Intron 2 of 6	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.544+1391T>C		intron_variant	Intron 2 of 7	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77588 AN: 151878 Hom.: 20865 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.522

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

GnomAD4 genome AF: 0.511 AC: 77664 AN: 151996 Hom.: 20898 Cov.: 32 AF XY: 0.500 AC XY: 37114 AN XY: 74280

African (AFR) AF: 0.665 AC: 27568 AN: 41438

American (AMR) AF: 0.460 AC: 7018 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 1996 AN: 3462

East Asian (EAS) AF: 0.292 AC: 1507 AN: 5154

South Asian (SAS) AF: 0.353 AC: 1702 AN: 4820

European-Finnish (FIN) AF: 0.341 AC: 3603 AN: 10568

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32450 AN: 67974

Other (OTH) AF: 0.516 AC: 1089 AN: 2110

Alfa AF: 0.491 Hom.: 68949

Bravo AF: 0.528

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Mutations in HNF1B gene are generally 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, this particular variant (rs4430796) of HNF1B gene was seen to be associated with Gestational Diabetes Mellitus and more studies are required in different ethnic groups to ascertain its significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.2
PhyloP100		0.11

Splicing

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

Other links and lift over

dbSNP: rs4430796; hg19: chr17-36098040;