rs148410446
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_016938.5(EFEMP2):āc.934A>Gā(p.Thr312Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000491 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_016938.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EFEMP2 | NM_016938.5 | c.934A>G | p.Thr312Ala | missense_variant | 9/11 | ENST00000307998.11 | |
EFEMP2 | NR_037718.2 | n.1059A>G | non_coding_transcript_exon_variant | 9/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EFEMP2 | ENST00000307998.11 | c.934A>G | p.Thr312Ala | missense_variant | 9/11 | 1 | NM_016938.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000795 AC: 121AN: 152168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000613 AC: 154AN: 251024Hom.: 0 AF XY: 0.000530 AC XY: 72AN XY: 135806
GnomAD4 exome AF: 0.000460 AC: 672AN: 1461538Hom.: 0 Cov.: 32 AF XY: 0.000439 AC XY: 319AN XY: 727080
GnomAD4 genome AF: 0.000795 AC: 121AN: 152286Hom.: 0 Cov.: 33 AF XY: 0.00107 AC XY: 80AN XY: 74460
ClinVar
Submissions by phenotype
Cutis laxa, autosomal recessive, type 1B Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 25, 2020 | The EFEMP2 c.934A>G; p.Thr312Ala variant (rs148410446), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.07 % (198 /282,392 alleles) in the Genome Aggregation Database. The threonine at codon 312 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.38). Due to limited information, the clinical significance of the p.Thr312Ala variant is uncertain at this time. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 03, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2024 | Variant summary: EFEMP2 c.934A>G (p.Thr312Ala) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251024 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EFEMP2 causing Autosomal Recessive Cutis Laxa (0.00061 vs 0.00071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.934A>G in individuals affected with Autosomal Recessive Cutis Laxa and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 305379). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 17, 2023 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2019 | This alteration is classified as 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at