rs377129682
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP5
This summary comes from the ClinGen Evidence Repository: The c.185A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 62 (p.(Asn62Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00019, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). Furthermore, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.185A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831682/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.185A>G | p.Asn62Ser | missense_variant | 1/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.185A>G | p.Asn62Ser | missense_variant | 1/10 | ||
HNF1A | NM_001406915.1 | c.185A>G | p.Asn62Ser | missense_variant | 1/9 | ||
HNF1A | XM_024449168.2 | c.185A>G | p.Asn62Ser | missense_variant | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.185A>G | p.Asn62Ser | missense_variant | 1/10 | 1 | NM_000545.8 | P4 | |
HNF1A-AS1 | ENST00000619441.1 | n.128+1691T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152012Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000128 AC: 30AN: 234674Hom.: 0 AF XY: 0.000117 AC XY: 15AN XY: 127964
GnomAD4 exome AF: 0.000196 AC: 285AN: 1457208Hom.: 0 Cov.: 35 AF XY: 0.000179 AC XY: 130AN XY: 724590
GnomAD4 genome ? AF: 0.000164 AC: 25AN: 152012Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74264
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 02, 2017 | - - |
Maturity onset diabetes mellitus in young Uncertain:1
Uncertain significance, 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. Sufficient evidence is found to confer the association of this particular variant rs377129682 with MODY3. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 62 of the HNF1A protein (p.Asn62Ser). This variant is present in population databases (rs377129682, gnomAD 0.02%). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 32910913). ClinVar contains an entry for this variant (Variation ID: 447485). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HNF1A function (PMID: 27899486, 32910913). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Monogenic diabetes Benign:1
Benign, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Jun 03, 2022 | The c.185A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 62 (p.(Asn62Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00019, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). Furthermore, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.185A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BA1, BP5. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at