rs41548013

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1208G) has been classified as Uncertain significance.

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

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

X-linked intellectual disability, van Esch type
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
X-linked reticulate pigmentary disorder
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

POLA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 587618.

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

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.:

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

GnomAD2 exomes

AF:

0.00396

AC:

710

AN:

179133

AF XY:

0.00369

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 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

African (AFR)

AF:

0.000799

AC:

AN:

26298

American (AMR)

AF:

0.00151

AC:

AN:

35100

Ashkenazi Jewish (ASJ)

AF:

0.000155

AC:

AN:

19336

East Asian (EAS)

AF:

0.00

AC:

AN:

30090

South Asian (SAS)

AF:

0.00281

AC:

151

AN:

53688

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

40464

Middle Eastern (MID)

AF:

0.000728

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.00889

AC:

7451

AN:

837845

Other (OTH)

AF:

0.00621

AC:

285

AN:

45896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

249

499

748

998

1247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

282

564

846

1128

1410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00401

AC:

448

AN:

111689

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

132

AN XY:

33881

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

30731

American (AMR)

AF:

0.00229

AC:

AN:

10495

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3552

South Asian (SAS)

AF:

0.00115

AC:

AN:

2607

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

6060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00705

AC:

375

AN:

53175

Other (OTH)

AF:

0.00197

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

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

PhyloP100

5.2

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

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over