chr12-120994264-C-A

Position:

• chr12-120994264-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3 PM2_Supporting PM1 PM5_Strong PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.814C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to serine at codon 272 (p.(Arg272Ser)) 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.949, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with diabetes, with five informative meioses in two families with MODY (PP1_Strong; internal lab contributors). Two other missense variants, c.814C>T (p.Arg272Cys) and c.815G>A (p.Arg272His), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg272Ser has a greater Grantham distance than p.Arg272His. (PM5_Strong). 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 (PMIDs: 31165087 and 18003757, internal lab contributors). One of these individuals had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). In summary, c.814C>A 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, PP1_Strong, PM5_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386966358/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: 1.79

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 Pathogenic. Variant got 12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.814C>A	p.Arg272Ser	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.814C>A	p.Arg272Ser	missense_variant	4/10
HNF1A	NM_001406915.1	c.814C>A	p.Arg272Ser	missense_variant	4/9
HNF1A	XM_024449168.2	c.814C>A	p.Arg272Ser	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.814C>A	p.Arg272Ser	missense_variant	4/10	1	NM_000545.8	P4

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

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 15, 2022

The c.814C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to serine at codon 272 (p.(Arg272Ser)) 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.949, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with diabetes, with five informative meioses in two families with MODY (PP1_Strong; internal lab contributors). Two other missense variants, c.814C>T (p.Arg272Cys) and c.815G>A (p.Arg272His), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg272Ser has a greater Grantham distance than p.Arg272His. (PM5_Strong). 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 (PMIDs: 31165087 and 18003757, internal lab contributors). One of these individuals had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). In summary, c.814C>A 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, PP1_Strong, PM5_Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.6	D;.;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0050	D;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.99	.;.;.;D
Vest4		0.97
MutPred		0.82		Loss of methylation at K273 (P = 0.0618);Loss of methylation at K273 (P = 0.0618);Loss of methylation at K273 (P = 0.0618);Loss of methylation at K273 (P = 0.0618);
MVP		1.0
MPC		2.2
ClinPred		0.99	D
GERP RS		3.9
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121432067; COSMIC: COSV57459326; COSMIC: COSV57459326;