rs201039488

Positions:

• chr12-120996922-C-CA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000545.8(HNF1A):​c.1309+184dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,506,614 control chromosomes in the GnomAD database, including 58 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (18 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (40 hom.)
• Consequence: HNF1A NM_000545.8 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.992

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 12-120996922-C-CA is Benign according to our data. Variant chr12-120996922-C-CA is described in ClinVar as [Benign]. Clinvar id is 135500.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 797 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.1309+184dup		intron_variant		ENST00000257555.11
HNF1A	NM_001306179.2	c.1309+184dup		intron_variant
HNF1A	NM_001406915.1	c.1309+184dup		intron_variant
HNF1A	XM_024449168.2	c.1309+184dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.1309+184dup		intron_variant		1	NM_000545.8	P4

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 797 AN: 151846 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00573 AC: 843 AN: 147196 Hom.: 11 AF XY: 0.00523 AC XY: 415 AN XY: 79328

Gnomad AFR exome AF: 0.000441

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.00525

Gnomad EAS exome AF: 0.0000917

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.0334

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00351

GnomAD4 exome AF: 0.00441 AC: 5968 AN: 1354650 Hom.: 40 Cov.: 23 AF XY: 0.00434 AC XY: 2910 AN XY: 670342

Gnomad4 AFR exome AF: 0.000615

Gnomad4 AMR exome AF: 0.00200

Gnomad4 ASJ exome AF: 0.00539

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000645

Gnomad4 FIN exome AF: 0.0309

Gnomad4 NFE exome AF: 0.00394

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.00524 AC: 797 AN: 151964 Hom.: 18 Cov.: 31 AF XY: 0.00626 AC XY: 465 AN XY: 74274

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0345

Gnomad4 NFE AF: 0.00494

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00437 Hom.: 3

Bravo AF: 0.00265

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maturity onset diabetes mellitus in young Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs201039488 with MODY3. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

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: rs201039488; hg19: chr12-121434725;