rs587778399

chr12-120999578-CAGCATCCAGCACCT-CGGCATCCAGCACC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000545.8(HNF1A):c.1720_1733delinsGGCATCCAGCACC(p.Ser574GlyfsTer86) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 5.45

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120999579-AGCATCCAGCACCT-GGCATCCAGCACC is Pathogenic according to our data. Variant chr12-120999579-AGCATCCAGCACCT-GGCATCCAGCACC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1687089.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.1720_1733delinsGGCATCCAGCACC	p.Ser574GlyfsTer86	frameshift_variant	9/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.1741_1754delinsGGCATCCAGCACC	p.Ser581GlyfsTer86	frameshift_variant	9/10
HNF1A	NM_001406915.1	c.1528_1541delinsGGCATCCAGCACC	p.Ser510GlyfsTer86	frameshift_variant	8/9
HNF1A	XM_024449168.2	c.1813_1826delinsGGCATCCAGCACC	p.Ser605GlyfsTer86	frameshift_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.1720_1733delinsGGCATCCAGCACC	p.Ser574GlyfsTer86	frameshift_variant	9/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 17, 2022

The c.1720_1733del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 578 (NM_000545.8), adding 82 novel amino acids before encountering a stop codon (p.(Leu578ArgfsTer82)). While this variant, located in exon 9 of 10, is predicted to cause a premature stop codon in a position that escapes nonsense mediated decay, it results in the loss of a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1733del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778399; hg19: chr12-121437382;