chrX-24966522-G-A

Variant names:

• chrX-24966522-G-A
• rs10521932
• NM_001330360.2:c.4262-29283G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330360.2(POLA1):​c.4262-29283G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0461 in 111,903 control chromosomes in the GnomAD database, including 232 homozygotes. There are 1,382 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.046 (232 hom., 1382 hem., cov: 23)
• Consequence: POLA1 NM_001330360.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.400
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLA1	NM_001330360.2	c.4262-29283G>A		intron_variant	Intron 36 of 36	ENST00000379068.8	NP_001317289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLA1	ENST00000379068.8	c.4262-29283G>A		intron_variant	Intron 36 of 36	5	NM_001330360.2	ENSP00000368358.3

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 5149 AN: 111852 Hom.: 231 Cov.: 23

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00729

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.00984

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.0251

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0356

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0461 AC: 5163 AN: 111903 Hom.: 232 Cov.: 23 AF XY: 0.0405 AC XY: 1382 AN XY: 34121

African (AFR) AF: 0.135 AC: 4152 AN: 30742

American (AMR) AF: 0.0211 AC: 223 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00984 AC: 26 AN: 2642

East Asian (EAS) AF: 0.000279 AC: 1 AN: 3589

South Asian (SAS) AF: 0.00749 AC: 20 AN: 2672

European-Finnish (FIN) AF: 0.00329 AC: 20 AN: 6080

Middle Eastern (MID) AF: 0.0275 AC: 6 AN: 218

European-Non Finnish (NFE) AF: 0.0123 AC: 656 AN: 53166

Other (OTH) AF: 0.0352 AC: 54 AN: 1534

Alfa AF: 0.0263 Hom.: 1143

Bravo AF: 0.0532

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.30
DANN	Benign	0.42
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10521932; hg19: chrX-24984639;