chrX-24699526-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001330360.2(POLA1):c.145G>A(p.Ala49Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000196 in 1,173,151 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000020 ( 0 hom. 4 hem. )
Consequence
POLA1
NM_001330360.2 missense
NM_001330360.2 missense
Scores
5
10
Clinical Significance
Conservation
PhyloP100: 4.07
Genes affected
POLA1 (HGNC:9173): (DNA polymerase alpha 1, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase, which together with a regulatory and two primase subunits, forms the DNA polymerase alpha complex. The catalytic subunit plays an essential role in the initiation of DNA replication. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.17644611).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLA1 | NM_001330360.2 | c.145G>A | p.Ala49Thr | missense_variant | 2/37 | ENST00000379068.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLA1 | ENST00000379068.8 | c.145G>A | p.Ala49Thr | missense_variant | 2/37 | 5 | NM_001330360.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000179 AC: 2AN: 111758Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33936
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000132 AC: 2AN: 151130Hom.: 0 AF XY: 0.0000235 AC XY: 1AN XY: 42536
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GnomAD4 exome AF: 0.0000198 AC: 21AN: 1061393Hom.: 0 Cov.: 25 AF XY: 0.0000119 AC XY: 4AN XY: 335025
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 04, 2021 | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with POLA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 43 of the POLA1 protein (p.Ala43Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Benign
Sift
Uncertain
D;.;D
Sift4G
Benign
T;T;T
Polyphen
P;.;P
Vest4
MutPred
Gain of phosphorylation at A49 (P = 0.0152);.;.;
MVP
MPC
0.40
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at