chr12-120978841-G-A

Position:

• chr12-120978841-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2_Supporting PM1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.73G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Alanine to Threonine at codon 25 (p.(Ala25Thr)) of transcript NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.73G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA160004/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 O:2
• Conservation: PhyloP100: 2.77

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 Uncertain_significance. Variant got 2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.73G>A	p.Ala25Thr	missense_variant	1/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.73G>A	p.Ala25Thr	missense_variant	1/10
HNF1A	NM_001406915.1	c.73G>A	p.Ala25Thr	missense_variant	1/9
HNF1A	XM_024449168.2	c.73G>A	p.Ala25Thr	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.73G>A	p.Ala25Thr	missense_variant	1/10	1	NM_000545.8	P4
HNF1A-AS1	ENST00000619441.1	n.128+1803C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461076 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 726868

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:2

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

Apr 01, 2022

The c.73G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Alanine to Threonine at codon 25 (p.(Ala25Thr)) of transcript NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.73G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_supporting, PM2_supporting. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Maturity onset diabetes mellitus in young Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs587778394 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	.;D;T;D;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T;T;T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.29	N;.;.;.;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.51	T;.;.;.;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;.;B
Vest4		0.063
MutPred		0.49		Loss of methylation at K23 (P = 0.1843);Loss of methylation at K23 (P = 0.1843);Loss of methylation at K23 (P = 0.1843);Loss of methylation at K23 (P = 0.1843);Loss of methylation at K23 (P = 0.1843);Loss of methylation at K23 (P = 0.1843);
MVP		0.69
MPC		0.16
ClinPred		0.42	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.58

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: rs587778394; hg19: chr12-121416644;