15-38351521-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_152594.3(SPRED1):c.1192G>A(p.Asp398Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,613,982 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D398Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_152594.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPRED1 | NM_152594.3 | c.1192G>A | p.Asp398Asn | missense_variant | 7/7 | ENST00000299084.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPRED1 | ENST00000299084.9 | c.1192G>A | p.Asp398Asn | missense_variant | 7/7 | 1 | NM_152594.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152130Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000430 AC: 108AN: 251248Hom.: 1 AF XY: 0.000280 AC XY: 38AN XY: 135786
GnomAD4 exome AF: 0.000108 AC: 158AN: 1461852Hom.: 1 Cov.: 33 AF XY: 0.0000853 AC XY: 62AN XY: 727236
GnomAD4 genome AF: 0.0000855 AC: 13AN: 152130Hom.: 0 Cov.: 33 AF XY: 0.0000808 AC XY: 6AN XY: 74300
ClinVar
Submissions by phenotype
Legius syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 09, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 26, 2020 | Variant summary: SPRED1 c.1192G>A (p.Asp398Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251248 control chromosomes, predominantly at a frequency of 0.0029 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 516 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPRED1 causing Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) phenotype (5.6e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1192G>A has been reported in the literature (Messiaen_2009). This report however, does not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome). In in vitro cell based assays (Elk-1 reporter assays and PC12 cell line assays), the variant was found to have wild type activity. One ClinVar submitter (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2020 | This variant is associated with the following publications: (PMID: 19920235) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at