Genetic Variant POLA1:p.Asp7Glu (chrX-24693982-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001330360.2(POLA1):c.21C>G(p.Asp7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000926 in 1,079,534 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D7D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

POLA1
NM_001330360.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.42

Publications

2 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
X-linked reticulate pigmentary disorder
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

POLA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033857435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330360.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLA1	NM_001330360.2	MANE Select	c.21C>G	p.Asp7Glu	missense	Exon 1 of 37	NP_001317289.1	A6NMQ1
POLA1	NM_001440806.1		c.21C>G	p.Asp7Glu	missense	Exon 1 of 38	NP_001427735.1
POLA1	NM_016937.4		c.21C>G	p.Asp7Glu	missense	Exon 1 of 37	NP_058633.2	P09884

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLA1	ENST00000379068.8	TSL:5 MANE Select	c.21C>G	p.Asp7Glu	missense	Exon 1 of 37	ENSP00000368358.3	A6NMQ1
POLA1	ENST00000379059.7	TSL:1	c.21C>G	p.Asp7Glu	missense	Exon 1 of 37	ENSP00000368349.3	P09884
POLA1	ENST00000933044.1		c.21C>G	p.Asp7Glu	missense	Exon 1 of 38	ENSP00000603103.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

146519

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.26e-7

AC:

AN:

1079534

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

351110

show subpopulations

African (AFR)

AF:

0.0000387

AC:

AN:

25829

American (AMR)

AF:

0.00

AC:

AN:

32950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19052

East Asian (EAS)

AF:

0.00

AC:

AN:

28986

South Asian (SAS)

AF:

0.00

AC:

AN:

51529

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39127

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4109

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

832590

Other (OTH)

AF:

0.00

AC:

AN:

45362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.012

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.45

M_CAP

Benign

0.0031

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.29

PhyloP100

-3.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.45

REVEL

Benign

0.012

Sift

Benign

0.49

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.13

MutPred

0.28

Loss of catalytic residue at G6 (P = 0.1971)

MVP

0.14

MPC

0.32

ClinPred

0.13

GERP RS

-8.7

PromoterAI

-0.038

Neutral

(source)

Varity_R

0.069

gMVP

0.047

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over