chrX-24699490-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_001330360.2(POLA1):c.109C>T(p.Arg37Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,177,478 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001330360.2 missense
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLA1 | NM_001330360.2 | c.109C>T | p.Arg37Cys | missense_variant | 2/37 | ENST00000379068.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLA1 | ENST00000379068.8 | c.109C>T | p.Arg37Cys | missense_variant | 2/37 | 5 | NM_001330360.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000181 AC: 2AN: 110592Hom.: 0 Cov.: 22 AF XY: 0.0000608 AC XY: 2AN XY: 32906
GnomAD3 exomes AF: 0.0000256 AC: 4AN: 156056Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 46654
GnomAD4 exome AF: 0.0000150 AC: 16AN: 1066886Hom.: 0 Cov.: 25 AF XY: 0.0000148 AC XY: 5AN XY: 338390
GnomAD4 genome ? AF: 0.0000181 AC: 2AN: 110592Hom.: 0 Cov.: 22 AF XY: 0.0000608 AC XY: 2AN XY: 32906
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This missense change has been observed in individual(s) with clinical features of POLA1-related conditions (PMID: 30392784). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 31 of the POLA1 protein (p.Arg31Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at