chr12-120997547-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP5BP7
This summary comes from the ClinGen Evidence Repository: The c.1383C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 461 (p.(Pro461=)) of NM_000545.8. This variant was identified in a patient with an alternate molecular basis for disease (BP5; ClinVar: SCV000595127.1, personal communication from Genetic Services Laboratory, University of Chicago). Additionally, this synonymous variant is not predicted by SpliceAI to impact splicing (BP7). The variant frequency fell between the ClinGen MDEP BS1 and PM2_Supporting cutoffs; therefore, neither was applied. In summary, c.1383C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BP5, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6832031/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1383C>T | p.Pro461Pro | synonymous_variant | Exon 7 of 10 | ENST00000257555.11 | NP_000536.6 | |
HNF1A | NM_001306179.2 | c.1383C>T | p.Pro461Pro | synonymous_variant | Exon 7 of 10 | NP_001293108.2 | ||
HNF1A | XM_024449168.2 | c.1383C>T | p.Pro461Pro | synonymous_variant | Exon 7 of 9 | XP_024304936.1 | ||
HNF1A | NM_001406915.1 | c.1309+805C>T | intron_variant | Intron 6 of 8 | NP_001393844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1383C>T | p.Pro461Pro | synonymous_variant | Exon 7 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152170Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249882Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135382
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461268Hom.: 0 Cov.: 38 AF XY: 0.0000344 AC XY: 25AN XY: 727000
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152288Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74482
ClinVar
Submissions by phenotype
Maturity onset diabetes mellitus in young Benign:2
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. However, more evidence is required to confer the association of this particular variant rs772756175 with MODY3. -
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not specified Benign:1
- -
Monogenic diabetes Benign:1
The c.1383C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 461 (p.(Pro461=)) of NM_000545.8. This variant was identified in a patient with an alternate molecular basis for disease (BP5; ClinVar: SCV000595127.1, personal communication from Genetic Services Laboratory, University of Chicago). Additionally, this synonymous variant is not predicted by SpliceAI to impact splicing (BP7). The variant frequency fell between the ClinGen MDEP BS1 and PM2_Supporting cutoffs; therefore, neither was applied. In summary, c.1383C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BP5, BP7. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at