1-21823667-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The NM_005529.7(HSPG2):c.12952C>T(p.Arg4318Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000558 in 1,613,670 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. R4318P) has been classified as Uncertain significance.
Frequency
Consequence
NM_005529.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HSPG2 | NM_005529.7 | c.12952C>T | p.Arg4318Trp | missense_variant | 96/97 | ENST00000374695.8 | |
LDLRAD2 | NM_001013693.3 | c.*1452G>A | 3_prime_UTR_variant | 5/5 | ENST00000344642.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HSPG2 | ENST00000374695.8 | c.12952C>T | p.Arg4318Trp | missense_variant | 96/97 | 1 | NM_005529.7 | P1 | |
LDLRAD2 | ENST00000344642.7 | c.*1452G>A | 3_prime_UTR_variant | 5/5 | 2 | NM_001013693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152098Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250734Hom.: 1 AF XY: 0.0000516 AC XY: 7AN XY: 135644
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461454Hom.: 2 Cov.: 41 AF XY: 0.0000261 AC XY: 19AN XY: 727042
GnomAD4 genome AF: 0.000335 AC: 51AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74424
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 22, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4318 of the HSPG2 protein (p.Arg4318Trp). This variant is present in population databases (rs3736358, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 447541). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 05, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 11, 2021 | The c.12952C>T (p.R4318W) alteration is located in exon 95 (coding exon 95) of the HSPG2 gene. This alteration results from a C to T substitution at nucleotide position 12952, causing the arginine (R) at amino acid position 4318 to be replaced by a tryptophan (W). The p.R4318W alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at