5-39341276-G-A
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting
The NM_001737.5(C9):c.346C>T(p.Arg116*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,613,954 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001737.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000572 AC: 87AN: 152076Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000868 AC: 218AN: 251092Hom.: 0 AF XY: 0.000803 AC XY: 109AN XY: 135748
GnomAD4 exome AF: 0.000658 AC: 962AN: 1461760Hom.: 14 Cov.: 32 AF XY: 0.000638 AC XY: 464AN XY: 727200
GnomAD4 genome AF: 0.000565 AC: 86AN: 152194Hom.: 1 Cov.: 32 AF XY: 0.000645 AC XY: 48AN XY: 74394
ClinVar
Submissions by phenotype
Complement component 9 deficiency Pathogenic:5
NM_001737.3:c.346C>T in the C9 gene has an allele frequency of 0.01 in East Asian subpopulation in the gnomAD database. The C9 c.346C>T (p.Arg116*) variant has been reported in five Japanese C9-deficient patients in homozygous states (PMID: 9703418; 11359403). Another study revealed that eight of the 10 C9D subjects were homozygous for this variant, which was assumed to be a founder mutation in Japanese (PMID: 9570574). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PS4. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with C9 deficiency (MIM#613825). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 224 heterozygotes, 0 homozygotes; v3: 87 heterozygotes, 1 homozygote). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with C9 deficiency and is regarded as a Japanese founder variant (ClinVar, PMID: 9570574). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
PVS1+PM3 -
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Complement component 9 deficiency;C3810042:Age related macular degeneration 15 Pathogenic:1
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not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg116*) in the C9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C9 are known to be pathogenic (PMID: 9144525, 9570574). This variant is present in population databases (rs121909592, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with complement component 9 (C9) deficiency (PMID: 9570574, 9703418, 12596049, 22190594). It is commonly reported in individuals of East Asian ancestry (PMID: 9570574, 9703418, 12596049, 22190594). This variant is also known as Arg95*. ClinVar contains an entry for this variant (Variation ID: 17040). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at