12-120994244-A-G

Position:

• chr12-120994244-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3 PM1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.794A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 265 (p.Tyr265Cys) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant also is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:30663027, internal lab contributors). Another missense variant, c.794A>C (p.Tyr265Ser), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.794A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386966196/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 8.86

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 4 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.794A>G	p.Tyr265Cys	missense_variant	4/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.794A>G	p.Tyr265Cys	missense_variant	4/10		NP_001293108.2
HNF1A	NM_001406915.1	c.794A>G	p.Tyr265Cys	missense_variant	4/9		NP_001393844.1
HNF1A	XM_024449168.2	c.794A>G	p.Tyr265Cys	missense_variant	4/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.794A>G	p.Tyr265Cys	missense_variant	4/10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 29, 2020	DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.794A>G, in exon 4 that results in an amino acid change, p.Tyr265Cys. This sequence change has been previously described in a patient with pre gestational diabetes mellitus who also carried another previously reported missense variant, c.862G>T, in the same gene (PMID: 30663027). This sequence change is absent from the large population databases (ExAC and gnomAD). The p.Tyr265Cys change affects a highly conserved amino acid residue located in a homeobox domain of the HNF1A protein that is known to be functional. The p.Tyr265Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2023	Identified in a non-obese pregnant woman with pregestational diabetes, however this woman also had a second variant in the HNF1A gene that could be contributing to her presentation (Zubkova et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12453420, 18003757, 30663027) -

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

May 02, 2022

The c.794A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 265 (p.Tyr265Cys) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant also is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 30663027, internal lab contributors). Another missense variant, c.794A>C (p.Tyr265Ser), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.794A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PP3, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.8	D;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.95
MutPred		0.69		Loss of MoRF binding (P = 0.0876);Loss of MoRF binding (P = 0.0876);Loss of MoRF binding (P = 0.0876);Loss of MoRF binding (P = 0.0876);
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		4.8
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-121432047;