NM_001379081.2:c.4499A>T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting
The NM_001379081.2(FREM1):c.4499A>T(p.Glu1500Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000538 in 1,562,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001379081.2 missense
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 |
---|---|---|---|---|---|---|---|---|
FREM1 | NM_001379081.2 | c.4499A>T | p.Glu1500Val | missense_variant | Exon 25 of 37 | ENST00000380880.4 | NP_001366010.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000374 AC: 57AN: 152218Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.0000290 AC: 6AN: 206884Hom.: 0 AF XY: 0.0000181 AC XY: 2AN XY: 110306
GnomAD4 exome AF: 0.0000199 AC: 28AN: 1409746Hom.: 0 Cov.: 34 AF XY: 0.0000158 AC XY: 11AN XY: 695032
GnomAD4 genome AF: 0.000368 AC: 56AN: 152336Hom.: 1 Cov.: 33 AF XY: 0.000443 AC XY: 33AN XY: 74496
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
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This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1500 of the FREM1 protein (p.Glu1500Val). This variant is present in population databases (rs281875280, gnomAD 0.02%). This missense change has been observed in individual(s) with metopic craniosynostosis (PMID: 21931569). ClinVar contains an entry for this variant (Variation ID: 30766). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Trigonocephaly 2 Pathogenic:1
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not specified Uncertain:1
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FREM1-related disorder Uncertain:1
The FREM1 c.4499A>T variant is predicted to result in the amino acid substitution p.Glu1500Val. This variant was reported in two unrelated individuals with craniosynostosis and was reported as de novo variant in one of the two individuals (Vissers et al 2011. PubMed ID: 21931569). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Oculotrichoanal syndrome;C2750433:BNAR syndrome;C3280974:Trigonocephaly 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at