chrX-24699427-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001330360.2(POLA1):c.46C>G(p.Leu16Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000607 in 1,153,121 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. L16P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000048 ( 0 hom. 1 hem. )

Consequence

POLA1
NM_001330360.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.719

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036536306).

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000048 (5/1042250) while in subpopulation AFR AF = 0.000122 (3/24574). AF 95% confidence interval is 0.0000323. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 25. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.46C>G	p.Leu16Val	missense splice_region	Exon 2 of 37	NP_001317289.1	A6NMQ1
POLA1	NM_001440806.1		c.46C>G	p.Leu16Val	missense splice_region	Exon 2 of 38	NP_001427735.1
POLA1	NM_016937.4		c.28C>G	p.Leu10Val	missense splice_region	Exon 2 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.46C>G	p.Leu16Val	missense splice_region	Exon 2 of 37	ENSP00000368358.3	A6NMQ1
POLA1	ENST00000379059.7	TSL:1	c.28C>G	p.Leu10Val	missense splice_region	Exon 2 of 37	ENSP00000368349.3	P09884
POLA1	ENST00000933044.1		c.28C>G	p.Leu10Val	missense splice_region	Exon 2 of 38	ENSP00000603103.1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110871

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000214

AC:

AN:

140191

AF XY:

0.0000265

show subpopulations

Gnomad AFR exome

AF:

0.0000933

Gnomad AMR exome

AF:

0.0000502

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:

0.000292

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1042250

Hom.:

Cov.:

AF XY:

0.00000307

AC XY:

AN XY:

325976

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000122

AC:

AN:

24574

American (AMR)

AF:

0.0000348

AC:

AN:

28704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17776

East Asian (EAS)

AF:

0.00

AC:

AN:

29346

South Asian (SAS)

AF:

0.00

AC:

AN:

43703

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3859

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

812130

Other (OTH)

AF:

0.0000230

AC:

AN:

43446

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0547993), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000180

AC:

AN:

110871

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

33199

show subpopulations

African (AFR)

AF:

0.0000656

AC:

AN:

30467

American (AMR)

AF:

0.00

AC:

AN:

10362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3552

South Asian (SAS)

AF:

0.00

AC:

AN:

2625

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53015

Other (OTH)

AF:

0.00

AC:

AN:

1496

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

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000828

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.0

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.25

M_CAP

Benign

0.0013

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.8

PhyloP100

0.72

PrimateAI

Benign

0.44

PROVEAN

Benign

0.040

REVEL

Benign

0.015

Sift

Benign

1.0

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.10

MutPred

0.48

Gain of sheet (P = 0.0827)

MVP

0.12

MPC

0.34

ClinPred

0.010

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.044

gMVP

0.062

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over