2-85551967-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate
The NM_000821.7(GGCX):āc.1454G>Cā(p.Arg485Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ).
Frequency
Consequence
NM_000821.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251372Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135856
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461598Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727120
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74304
ClinVar
Submissions by phenotype
Vitamin K-dependent clotting factors, combined deficiency of, type 1 Pathogenic:1
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not provided Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 485 of the GGCX protein (p.Arg485Pro). This variant is present in population databases (rs121909676, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive vitamin K-dependent clotting factors deficiency (PMID: 15287948, 16905958, 34816548). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 16197). 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. Experimental studies have shown that this missense change affects GGCX function (PMID: 27394683, 34816548). 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