rs41548013

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001330360.2(POLA1):c.3622G>C(p.Asp1208His) variant causes a missense change. The variant allele was found at a frequency of 0.00705 in 1,204,526 control chromosomes in the GnomAD database, including 32 homozygotes. There are 2,709 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 1 hom., 132 hem., cov: 23)

Exomes 𝑓: 0.0074 ( 31 hom. 2577 hem. )

Consequence

POLA1
NM_001330360.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.23

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007820755).

BP6

Variant X-24826487-G-C is Benign according to our data. Variant chrX-24826487-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587618.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chrX-24826487-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00401 (448/111689) while in subpopulation NFE AF= 0.00705 (375/53175). AF 95% confidence interval is 0.00646. There are 1 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 132 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLA1	NM_001330360.2 link	c.3622G>C	p.Asp1208His	missense_variant	Exon 32 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.3622G>C	p.Asp1208His	missense_variant	Exon 32 of 37	5	NM_001330360.2	ENSP00000368358.3		A6NMQ1

Frequencies

GnomAD3 genomes

AF:

0.00401

AC:

448

AN:

111634

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

132

AN XY:

33816

show subpopulations

Gnomad AFR

AF:

0.00127

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00115

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00705

Gnomad OTH

AF:

0.00199

GnomAD3 exomes

AF:

0.00396

AC:

710

AN:

179133

Hom.:

AF XY:

0.00369

AC XY:

236

AN XY:

63875

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.000135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00704

Gnomad OTH exome

AF:

0.00452

GnomAD4 exome

AF:

0.00736

AC:

8043

AN:

1092837

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

2577

AN XY:

358409

show subpopulations

Gnomad4 AFR exome

AF:

0.000799

Gnomad4 AMR exome

AF:

0.00151

Gnomad4 ASJ exome

AF:

0.000155

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00281

Gnomad4 FIN exome

AF:

0.00188

Gnomad4 NFE exome

AF:

0.00889

Gnomad4 OTH exome

AF:

0.00621

GnomAD4 genome

AF:

0.00401

AC:

448

AN:

111689

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

132

AN XY:

33881

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00115

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00705

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.00575

Hom.:

Bravo

AF:

0.00422

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00762

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00758

AC:

ExAC

AF:

0.00400

AC:

486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked reticulate pigmentary disorder

Uncertain:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

.;.;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.0078

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

.;.;L

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.0

D;.;D

REVEL

Benign

0.16

Sift

Uncertain

0.011

D;.;D

Sift4G

Uncertain

0.041

D;D;D

Polyphen

0.95

.;.;P

Vest4

0.059

MVP

0.46

MPC

0.98

ClinPred

0.031

GERP RS

4.7

Varity_R

0.47

gMVP

0.29

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