rs587780356

Positions:

• chr12-120996547-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

This summary comes from the ClinGen Evidence Repository: The c.1114G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 372 (p.(Ala372Thr)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1114G>A 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 6/4/2021): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA231160/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 O:1
• Conservation: PhyloP100: 5.55

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 2 ACMG points.

• PM2: 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.1114G>A	p.Ala372Thr	missense_variant	6/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1114G>A	p.Ala372Thr	missense_variant	6/10		NP_001293108.2
HNF1A	NM_001406915.1	c.1114G>A	p.Ala372Thr	missense_variant	6/9		NP_001393844.1
HNF1A	XM_024449168.2	c.1114G>A	p.Ala372Thr	missense_variant	6/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1114G>A	p.Ala372Thr	missense_variant	6/10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other: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

Dec 31, 2021

The c.1114G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to threonine at codon 372 (p.(Ala372Thr)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.1114G>A 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 6/4/2021): PM2_Supporting. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 17, 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 rs587780356 with MODY3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Uncertain	0.43	.;T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	0.00020	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.67	N;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.36	T;.;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.36	.;.;.;B
Vest4		0.34
MutPred		0.38		Gain of glycosylation at A372 (P = 0.0257);Gain of glycosylation at A372 (P = 0.0257);Gain of glycosylation at A372 (P = 0.0257);Gain of glycosylation at A372 (P = 0.0257);
MVP		0.76
MPC		0.14
ClinPred		0.34	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs587780356; hg19: chr12-121434350;