chr9-134815988-G-A
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1
The NM_000093.5(COL5A1):c.4122G>A(p.Thr1374Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,610 control chromosomes in the GnomAD database, including 19,278 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000093.5 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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COL5A1 | NM_000093.5 | c.4122G>A | p.Thr1374Thr | splice_region_variant, synonymous_variant | Exon 52 of 66 | ENST00000371817.8 | NP_000084.3 | |
COL5A1 | NM_001278074.1 | c.4122G>A | p.Thr1374Thr | splice_region_variant, synonymous_variant | Exon 52 of 66 | NP_001265003.1 | ||
COL5A1 | XM_017014266.3 | c.4122G>A | p.Thr1374Thr | splice_region_variant, synonymous_variant | Exon 52 of 65 | XP_016869755.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.4122G>A | p.Thr1374Thr | splice_region_variant, synonymous_variant | Exon 52 of 66 | 1 | NM_000093.5 | ENSP00000360882.3 | ||
COL5A1 | ENST00000371820.4 | c.4122G>A | p.Thr1374Thr | splice_region_variant, synonymous_variant | Exon 52 of 66 | 2 | ENSP00000360885.4 |
Frequencies
GnomAD3 genomes AF: 0.140 AC: 21362AN: 152044Hom.: 1606 Cov.: 33
GnomAD3 exomes AF: 0.147 AC: 36952AN: 251360Hom.: 2888 AF XY: 0.147 AC XY: 19954AN XY: 135876
GnomAD4 exome AF: 0.153 AC: 223574AN: 1461448Hom.: 17670 Cov.: 34 AF XY: 0.153 AC XY: 111168AN XY: 727038
GnomAD4 genome AF: 0.141 AC: 21386AN: 152162Hom.: 1608 Cov.: 33 AF XY: 0.139 AC XY: 10307AN XY: 74390
ClinVar
Submissions by phenotype
not specified Benign:4
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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not provided Benign:3
Variant summary: The COL5A1 c.4122G>A (p.Thr1374Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict weakening the canonical donor cite. However, these predictions have yet to be confirmed by functional studies. This variant was found in 17922/121286 control chromosomes (1465 homozygotes) at a frequency of 0.1477664, which is approximately 118213 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
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Ehlers-Danlos syndrome, classic type, 1 Benign:2
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Fibromuscular dysplasia, multifocal Benign:1
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Familial thoracic aortic aneurysm and aortic dissection Benign:1
This alteration is classified as 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. -
Ehlers-Danlos syndrome type 7A Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at