12-120993532-C-G

Position:

• chr12-120993532-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.539C>G variant in the HNF1 homeobox A gene, HNF1A causes an amino acid change of alanine to glycine at codon 180 (p.(Ala180Gly)) of NM_000545.8. 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, and sensitive to sulfonylurea treatment) (PP4_Moderate; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.539C>T (p.Ala180Val) has been classified as a likely benign by the ClinGen MDEP; therefore, PM5 will not be applied. This variant has a REVEL score of 0.492, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.539C>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/111/2023): PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386963548/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U: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]

HNF1A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• 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/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.539C>G	p.Ala180Gly	missense_variant	3/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.539C>G	p.Ala180Gly	missense_variant	3/10		NP_001293108.2
HNF1A	NM_001406915.1	c.539C>G	p.Ala180Gly	missense_variant	3/9		NP_001393844.1
HNF1A	XM_024449168.2	c.539C>G	p.Ala180Gly	missense_variant	3/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.539C>G	p.Ala180Gly	missense_variant	3/10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jul 29, 2024

The c.539C>G variant in the HNF1 homeobox A gene, HNF1A causes an amino acid change of alanine to glycine at codon 180 (p.(Ala180Gly)) of NM_000545.8. 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, and sensitive to sulfonylurea treatment) (PP4_Moderate; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.539C>T (p.Ala180Val) has been classified as a likely benign by the ClinGen MDEP; therefore, PM5 will not be applied. This variant has a REVEL score of 0.492, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.539C>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/111/2023): PP4_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;T;T;T;.
Eigen	Benign	-0.093
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N;.;.;.;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.091	T;.;.;.;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;.;B
Vest4		0.55
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.88
MPC		1.7
ClinPred		0.97	D
GERP RS		5.0
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121431335;