chr7-93131254-A-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_152703.5(SAMD9L):c.4718T>C(p.Ile1573Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000041 in 1,585,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1573N) has been classified as Likely benign.
Frequency
Consequence
NM_152703.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SAMD9L | NM_152703.5 | c.4718T>C | p.Ile1573Thr | missense_variant | 5/5 | ENST00000318238.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SAMD9L | ENST00000318238.9 | c.4718T>C | p.Ile1573Thr | missense_variant | 5/5 | 1 | NM_152703.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000310 AC: 7AN: 225658Hom.: 0 AF XY: 0.0000410 AC XY: 5AN XY: 121908
GnomAD4 exome AF: 0.0000432 AC: 62AN: 1433770Hom.: 0 Cov.: 32 AF XY: 0.0000477 AC XY: 34AN XY: 712200
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 07, 2021 | DNA sequence analysis of the SAMD9L gene demonstrated a sequence change, c.4718T>C, in exon 5 that results in an amino acid change, p.Ile1573Thr. This sequence change does not appear to have been previously described in individuals with SAMD9L-related disorders and has been described in the gnomAD database in 7 individuals with an overall population frequency of 0.003% (dbSNP rs371764964). The p.Ile1573Thr change affects a moderately conserved amino acid residue located in a domain of the SAMD9L protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile1573Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile1573Thr change remains unknown at this time. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 14, 2022 | The c.4718T>C (p.I1573T) alteration is located in exon 5 (coding exon 1) of the SAMD9L gene. This alteration results from a T to C substitution at nucleotide position 4718, causing the isoleucine (I) at amino acid position 1573 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1573 of the SAMD9L protein (p.Ile1573Thr). This variant is present in population databases (rs371764964, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SAMD9L-related conditions. ClinVar contains an entry for this variant (Variation ID: 1336548). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SAMD9L protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at