rs137853245

chr12-120994277-C-Achr12-120994277-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000545.8(HNF1A):c.827C>A(p.Ala276Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A276G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U: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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120994277-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36832.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 12-120994277-C-A is Pathogenic according to our data. Variant chr12-120994277-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 14945.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-120994277-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.827C>A	p.Ala276Asp	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.827C>A	p.Ala276Asp	missense_variant	4/10
HNF1A	NM_001406915.1	c.827C>A	p.Ala276Asp	missense_variant	4/9
HNF1A	XM_024449168.2	c.827C>A	p.Ala276Asp	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.827C>A	p.Ala276Asp	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248546 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134644

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461078 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726786

Gnomad4 AFR exome AF: 0.0000598

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2017	The A276D variant has been reported previously in association with MODY (Bjørkhaug et al., 2003; Bellanné-Chantelot et al., 2008). The variant is observed in 1/8770 (0.01%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). A276D is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (A276G) and in nearby residues (R271W/G/Q, R272S/H, K273N, K280E, L281P) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 14, 2021	DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.827C>A, in exon 4 that results in an amino acid change, p.Ala276Asp. This sequence change has been described in gnomAD with a low frequency of 0.013% in the African/African American sub-population (dbSNP rs137853245). The p.Ala276Asp change affects a highly conserved amino acid residue located in a domain of the HNF1A protein that is known to be functional. The p.Ala276Asp substitution appears to be damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This particular sequence change has been previously reported in an individual with HNF1A-related diabetes (PMID: 12574234). A different amino acid change at this same positon (p.Ala276Gly) has also been reported in individuals with HNF1A-related diabetes (PMIDs: 18003757, 24097065, 27899486). Functional studies have demonstrated that the p.Ala276Asp variant may slightly impact protein function (PMID: 12574234). In summary this sequence change has been interpreted as likely pathogenic. -

Monogenic diabetes Pathogenic:1 Uncertain:1

Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Apr 18, 2022	The c.827C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to aspartic acid at codon 276 (p.(Ala276Asp)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody-negative, and response to low-dose sulfonylurea (PP4_Moderate, internal lab contributors). Another missense variant, c.827C>G (p.Ala276Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Also, the variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). Functional studies demonstrated abnormal nuclear localization, DNA binding less than 40% of wildtype, and normal transactivation (PS3_Supporting; PMID:12574234). This variant is absent from the gnomAD European non-Finnish population, but two copies are present in the African population; therefore PM2_Supporting cannot be applied. This variant was identified in at least 12 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 12574234, internal lab contributors). In summary, c.827C>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): PP1_Strong, PP4_Moderate, PP3, PM1_Supporting, PM5_Supporting, PS3_Supporting. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ala276Asp variant in HNF1A has been reported in at least 2 individuals with monogenic diabetes (PMID: 18003757, 12574234), and has been identified in 0.01% (2/15696) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137853245). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as likely pathogenic and pathogenic (Variation ID#: rs137853245). In vitro functional studies provide some evidence that the p.Ala276Asp variant may slightly impact protein function (PMID: 12574234). However, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3, PS3_supporting, PS4_supporting (Richards 2015). -

Hyperinsulinism due to HNF1A deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Jan 31, 2020

The p.Ala276Asp variant replaces the alanine with aspartic acid at position 276 of the protein. This variant has previously been reported as pathogenic in two individuals diagnosed with MODY (PMID: 12574234, 24097065). The p.Ala276Asp is not a common variant in the general population (observed in 2 of 248,546 alleles in the Genome Aggregation Database). This variant has been interpreted as likely pathogenic by an outside laboratory (ClinVar Variation ID: 29984). In silico tools predict this alteration is damaging (DANN, MutationTaster, SIFT). Further supporting pathogenicity, a different missense change at the same residue (p.Ala276Gly) has been reported in an individual with MODY (NBK500456). -

Maturity-onset diabetes of the young type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.94
MutPred		0.73		Loss of MoRF binding (P = 0.0491);Loss of MoRF binding (P = 0.0491);Loss of MoRF binding (P = 0.0491);Loss of MoRF binding (P = 0.0491);
MVP		0.99
MPC		0.67
ClinPred		0.99	D
GERP RS		4.8
gMVP		0.99

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: rs137853245; hg19: chr12-121432080; COSMIC: COSV99983202; COSMIC: COSV99983202;