Genetic Variant NM_001330360.2:c.83G>C (chrX-24699464-G-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001330360.2(POLA1):c.83G>C(p.Arg28Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000468 in 1,069,157 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000047 ( 0 hom. 3 hem. )

Consequence

POLA1
NM_001330360.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.01

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.4219873).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLA1	NM_001330360.2 link	c.83G>C	p.Arg28Pro	missense_variant	Exon 2 of 37	ENST00000379068.8	NP_001317289.1	A6NMQ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLA1	ENST00000379068.8 link	c.83G>C	p.Arg28Pro	missense_variant	Exon 2 of 37	5	NM_001330360.2	ENSP00000368358.3		A6NMQ1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000468

AC:

AN:

1069157

Hom.:

Cov.:

AF XY:

0.00000880

AC XY:

AN XY:

340923

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000607

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 22 of the POLA1 protein (p.Arg22Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLA1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

.;.;D

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;.;M

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.6

D;.;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0040

D;.;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.49

MutPred

0.40

Gain of glycosylation at R28 (P = 0.0082);.;.;

MVP

0.44

MPC

1.3

ClinPred

0.99

GERP RS

5.0

Varity_R

0.91

gMVP

0.50

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over