rs552505619
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The ENST00000268097.10(HEXA):c.1073C>T(p.Thr358Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,599,058 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T358T) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000268097.10 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.1073C>T | p.Thr358Met | missense_variant, splice_region_variant | 9/14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.1106C>T | p.Thr369Met | missense_variant, splice_region_variant | 9/14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.1115C>T | splice_region_variant, non_coding_transcript_exon_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.1073C>T | p.Thr358Met | missense_variant, splice_region_variant | 9/14 | 1 | NM_000520.6 | ENSP00000268097 | P1 | |
ENST00000570175.1 | n.1577+1251G>A | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152072Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000223 AC: 56AN: 251234Hom.: 2 AF XY: 0.000280 AC XY: 38AN XY: 135792
GnomAD4 exome AF: 0.000169 AC: 244AN: 1446868Hom.: 4 Cov.: 29 AF XY: 0.000214 AC XY: 154AN XY: 720738
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74398
ClinVar
Submissions by phenotype
Tay-Sachs disease Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 18, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 358 of the HEXA protein (p.Thr358Met). This variant is present in population databases (rs552505619, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. ClinVar contains an entry for this variant (Variation ID: 582729). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at