X-24699463-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001330360.2(POLA1):c.82C>T(p.Arg28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000426 in 1,174,908 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. R28Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000038 ( 0 hom. 0 hem. )

Consequence

POLA1
NM_001330360.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.05

Variant links:

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]

POLA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35480696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLA1	NM_001330360.2 linkuse as main transcript	c.82C>T	p.Arg28Trp	missense_variant	2/37	ENST00000379068.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLA1	ENST00000379068.8 linkuse as main transcript	c.82C>T	p.Arg28Trp	missense_variant	2/37	5	NM_001330360.2	A1

Frequencies

GnomAD3 genomes

AF:

0.00000914

AC:

AN:

109398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31974

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000375

AC:

AN:

1065510

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

338632

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000298

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000365

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000914

AC:

AN:

109398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31974

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 12, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 22 of the POLA1 protein (p.Arg22Trp). 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 variant has not been reported in the literature in individuals affected with POLA1-related conditions. 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

Cadd

Uncertain

Dann

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.7

D;.;D

REVEL

Benign

0.21

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.42

MutPred

0.41

Gain of loop (P = 0.0502);.;.;

MVP

0.54

MPC

1.1

ClinPred

0.97

GERP RS

4.2

Varity_R

0.74

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over