12-120978769-A-T

Variant names:

• chr12-120978769-A-T
• rs193922592
• NM_000545.8:c.1A>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1A>T variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1Leu) of transcript NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting and PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386951973/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 initiator_codon
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.33

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]

HNF1A-AS1 (HGNC:26785): (HNF1A antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Mar 04, 2022

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1A>T variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1Leu) of transcript NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting and PP4_Moderate. -

not provided Pathogenic:1

Jun 27, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.38	.;T;T;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PROVEAN	Benign	-1.7	N;.;.;N;N;N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;T;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.65	.;.;.;.;.;P
Vest4		0.90
MutPred		0.90		Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);Loss of methylation at K4 (P = 0.0899);
MVP		0.99
ClinPred		1.0	D
GERP RS		4.3
gMVP		0.64

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: rs193922592; hg19: chr12-121416572;