chr12-120994238-G-T

Variant names:

• chr12-120994238-G-T
• rs1057520504
• NM_000545.8:c.788G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM5_Strong PS3_Supporting PM2_Supporting PP3 PP1 PM1

This summary comes from the ClinGen Evidence Repository: The c.788G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to leucine at codon 263 (p. (Arg263Leu) of transcript, e.g. 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). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.933, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1(PM2_Supporting). Two other missense variants, c.787C>T (p.Arg263Cys) and c.788G>A (p.Arg263His), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg263Leu has a greater Grantham distance than p.Arg263His (PM5_Strong). Functional studies demonstrated the p.Arg263Leu protein has no DNA binding activity, indicating that this variant impacts protein function (PS3_Supporting, PMID:12712243). This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID:12712243). This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (MODY probability calculator result >50%); however, HNF1A was not tested, and PP4 is not applied (PMID:12712243). In summary, c.790G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PM5_Strong, PS3_Supporting, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386966158/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 9.50

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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 rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.788G>T	p.Arg263Leu	missense_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.788G>T	p.Arg263Leu	missense_variant	Exon 4 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.788G>T	p.Arg263Leu	missense_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.788G>T	p.Arg263Leu	missense_variant	Exon 4 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.788G>T	p.Arg263Leu	missense_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Apr 14, 2022

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.788G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to leucine at codon 263 (p. (Arg263Leu) of transcript, e.g. 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). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.933, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1(PM2_Supporting). Two other missense variants, c.787C>T (p.Arg263Cys) and c.788G>A (p.Arg263His), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg263Leu has a greater Grantham distance than p.Arg263His (PM5_Strong). Functional studies demonstrated the p.Arg263Leu protein has no DNA binding activity, indicating that this variant impacts protein function (PS3_Supporting, PMID: 12712243). This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID: 12712243). This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (MODY probability calculator result >50%); however, HNF1A was not tested, and PP4 is not applied (PMID: 12712243). In summary, c.790G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PP3, PM5_Strong, PS3_Supporting, PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.88	D
PhyloP100		9.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.6	D;.;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0090	D;.;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.94	.;.;.;P
Vest4		0.95
MutPred		0.85		Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		4.8
gMVP		0.98
Mutation Taster		=0/100	disease causing

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

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Other links and lift over

dbSNP: rs1057520504; hg19: chr12-121432041; COSMIC: COSV57466458; COSMIC: COSV57466458;