rs886039544

Positions:

• chr12-120994229-C-G
• chr12-120994229-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_Supporting PM1_Supporting PM5_Supporting PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The c.779C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to arginine at codon 260 (p.(Thr260Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) 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). 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 negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Arg (PM5_Supporting). In summary, c.779C>G p.Thr260Arg meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386966083/MONDO:0015967/085

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 7.49

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_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.779C>G	p.Thr260Arg	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.779C>G	p.Thr260Arg	missense_variant	4/10
HNF1A	NM_001406915.1	c.779C>G	p.Thr260Arg	missense_variant	4/9
HNF1A	XM_024449168.2	c.779C>G	p.Thr260Arg	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.779C>G	p.Thr260Arg	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Sep 19, 2023

The c.779C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to arginine at codon 260 (p.(Thr260Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) 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). 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 negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Arg (PM5_Supporting). In summary, c.779C>G p.Thr260Arg meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.025	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.99
MutPred		0.82		Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		4.8
gMVP		0.98

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: chr12-121432032;