3-93973667-T-C
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000313.4(PROS1):c.76+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,613,266 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000313.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PROS1 | NM_000313.4 | c.76+7A>G | splice_region_variant, intron_variant | Intron 1 of 14 | ENST00000394236.9 | NP_000304.2 | ||
PROS1 | NM_001314077.2 | c.76+7A>G | splice_region_variant, intron_variant | Intron 1 of 15 | NP_001301006.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000539 AC: 82AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000769 AC: 190AN: 246970Hom.: 1 AF XY: 0.000738 AC XY: 99AN XY: 134094
GnomAD4 exome AF: 0.000428 AC: 625AN: 1461048Hom.: 4 Cov.: 30 AF XY: 0.000396 AC XY: 288AN XY: 726830
GnomAD4 genome AF: 0.000539 AC: 82AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40AN XY: 74364
ClinVar
Submissions by phenotype
Thrombophilia due to protein S deficiency, autosomal dominant Uncertain:1Benign:1
The c.76+7A>G variant has been reported in two studies in patients with protein S deficiency in which it was identified in a heterozygous state in one patient who was also heterozygous for the Factor V Leiden variant, and as the only variant in a heterozygous state in four patients including one proband and two first-degree relatives who all showed reduced levels of protein S (Simmonds et al. 1996; Makris et al. 2000; Klostermeier et al. 2015). The c.76+7A>G variant was not found among 70 normal control alleles but is reported at a frequency of is 0.001 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The c.76+7A>G variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for protein S deficiency. -
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not provided Uncertain:1Benign:1
PROS1: BP4 -
BS1, PP1 -
Protein S deficiency disease Uncertain:1
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PROS1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Thrombophilia due to protein S deficiency, autosomal recessive Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at