chr3-149178609-C-G
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2
The NM_000096.4(CP):āc.2684G>Cā(p.Gly895Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,726 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000096.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00156 AC: 237AN: 151782Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00152 AC: 380AN: 250058Hom.: 0 AF XY: 0.00160 AC XY: 217AN XY: 135310
GnomAD4 exome AF: 0.00185 AC: 2703AN: 1459826Hom.: 3 Cov.: 31 AF XY: 0.00186 AC XY: 1354AN XY: 726376
GnomAD4 genome AF: 0.00156 AC: 237AN: 151900Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110AN XY: 74260
ClinVar
Submissions by phenotype
Deficiency of ferroxidase Pathogenic:1Uncertain:4Benign:1
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not provided Uncertain:5Benign:1
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G876A); This variant is associated with the following publications: (PMID: 27753142, 28968711, 18293024, 16629161, 34426522, 31785789, 33774058, 34274368, 36233161, 37784196, 32235485, 36757662) -
CP: PP3, BP2, BS1 -
not specified Uncertain:1Benign:1
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Variant summary: CP c.2684G>C (p.Gly895Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250058 control chromosomes (gnomAD), predominantly at a frequency of 0.0024 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Ten ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance, one as likely pathogenic, and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Hypoceruloplasminemia Pathogenic:1
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (DOI:10.1016/j.mgene.2021.100905) - PS3_supporting. The c.2684G>C;p.(Gly895Ala) missense variant has been observed in affected individual(s) (PMID: 32235485; 27753142; 20301666; https://doi.org/10.1016/j.mgene.2021.100905) - PS4_supporting. The variant is present at low allele frequencies population databases (rs139633388 - gnomAD 0.01561%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly895Ala) was detected in trans with a pathogenic variant (PMID: 32235485; 27753142; https://doi.org/10.1016/j.mgene.2021.100905) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32235485) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
CP-related disorder Uncertain:1
The CP c.2684G>C variant is predicted to result in the amino acid substitution p.Gly895Ala. This variant has been reported in patients with aceruloplasminemia, although conclusive evidence of pathogenicity was not presented (reported as G876A in Kono et al. 2006. PubMed ID: 16629161; Vila Cuenca et al. 2020. PubMed ID: 32235485). This variant is reported in 0.25% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at