15-38351531-G-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_StrongBP6BS2
The NM_152594.3(SPRED1):c.1202G>T(p.Cys401Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,984 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_152594.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251246Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135784
GnomAD4 exome AF: 0.0000739 AC: 108AN: 1461862Hom.: 0 Cov.: 33 AF XY: 0.0000743 AC XY: 54AN XY: 727236
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: SPRED1 c.1202G>T (p.Cys401Phe) results in a non-conservative amino acid change located in the Sprouty domain (IPR007875) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251246 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1202G>T has been reported in the literature as a VUS in the settings of multigene panel testing in one individual within a cohort of Finnish individuals affected with dilated cardiomyopathy (DCM) (example, Akinrinade_2015). The report does not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Legius syndrome Uncertain:1
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 401 of the SPRED1 protein (p.Cys401Phe). This variant is present in population databases (rs779058019, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 26084686). ClinVar contains an entry for this variant (Variation ID: 468791). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt SPRED1 function with a negative predictive value of 95%. 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. -
Cardiovascular phenotype Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at