12-120993532-C-T

Variant names:

• chr12-120993532-C-T
• rs1060499866
• NM_000545.8:c.539C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. BS3_Supporting BS2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.539C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 180 (p.(Ala180Val)) of NM_000545.8. Functional studies demonstrated the p.Ala180Val protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID:28934671) (BS3_Supporting). Additionally, this variant was identified in the homozygous state in a normoglycemic individual (PMID:28934671) (BS2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.539C>T meets the criteria to be classified as likely benign for monogenic diabetes, though it likely influences diabetes risk. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS3_Supporting, BS2, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16609762/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:1
• Conservation: PhyloP100: 5.61

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 -4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.539C>T	p.Ala180Val	missense_variant	Exon 3 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.539C>T	p.Ala180Val	missense_variant	Exon 3 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.539C>T	p.Ala180Val	missense_variant	Exon 3 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.539C>T	p.Ala180Val	missense_variant	Exon 3 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.539C>T	p.Ala180Val	missense_variant	Exon 3 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461778 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in one individual with MODY. It is not present in ExAC, gnomAD, or ClinVar. It is predicted to be tolerated by prediction tools. -

Monogenic diabetes Benign:1

Jul 29, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.539C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 180 (p.(Ala180Val)) of NM_000545.8. Functional studies demonstrated the p.Ala180Val protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 28934671) (BS3_Supporting). Additionally, this variant was identified in the homozygous state in a normoglycemic individual (PMID: 28934671) (BS2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.539C>T meets the criteria to be classified as likely benign for monogenic diabetes, though it likely influences diabetes risk. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS3_Supporting, BS2, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;T;T;T;.
Eigen	Benign	0.062
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T;T;T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;.;.;.;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.010	D;.;.;.;D;D
Sift4G	Uncertain	0.042	D;T;T;D;D;D
Polyphen		0.025	.;.;.;.;.;B
Vest4		0.73
MutPred		0.33		Loss of disorder (P = 0.096);Loss of disorder (P = 0.096);Loss of disorder (P = 0.096);Loss of disorder (P = 0.096);Loss of disorder (P = 0.096);Loss of disorder (P = 0.096);
MVP		0.88
MPC		1.2
ClinPred		0.79	D
GERP RS		5.0
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1060499866; hg19: chr12-121431335; COSMIC: COSV57462802; COSMIC: COSV57462802;