rs571278160
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1PM2PM5PP5_ModerateBP4
The NM_000312.4(PROC):c.970G>A(p.Gly324Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G324R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000312.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROC | NM_000312.4 | c.970G>A | p.Gly324Ser | missense_variant | 9/9 | ENST00000234071.8 | |
LOC105373608 | XR_007087228.1 | n.1041-266C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROC | ENST00000234071.8 | c.970G>A | p.Gly324Ser | missense_variant | 9/9 | 1 | NM_000312.4 | P1 | |
PROC | ENST00000409048.1 | c.1072G>A | p.Gly358Ser | missense_variant | 7/7 | 5 | |||
PROC | ENST00000402125.2 | c.295G>A | p.Gly99Ser | missense_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251216Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135834
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461582Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39AN XY: 727098
GnomAD4 genome ? AF: 0.0000459 AC: 7AN: 152362Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74508
ClinVar
Submissions by phenotype
Thrombophilia due to protein C deficiency, autosomal dominant Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 17, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly324 amino acid residue in PROC. Other variant(s) that disrupt this residue have been observed in individuals with PROC-related conditions (PMID: 7792728), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 568761). This variant is also known as G282S. This missense change has been observed in individual(s) with clinical features of protein C deficiency (PMID: 7831652, 27517348; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs571278160, gnomAD 0.06%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 324 of the PROC protein (p.Gly324Ser). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at