rs869312979

Variant names:

• chrX-24726579-A-G
• rs869312979
• NM_001330360.2:c.1393-354A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-24726579-A-G
• chrX-24726579-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001330360.2(POLA1):​c.1393-354A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: POLA1 NM_001330360.2 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.605

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-24726579-A-G is Pathogenic according to our data. Variant chrX-24726579-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 224980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLA1	NM_001330360.2	c.1393-354A>G		intron_variant	Intron 13 of 36	ENST00000379068.8	NP_001317289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLA1	ENST00000379068.8	c.1393-354A>G		intron_variant	Intron 13 of 36	5	NM_001330360.2	ENSP00000368358.3

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked reticulate pigmentary disorder Pathogenic:2

Mar 25, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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SNPedia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

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not provided Pathogenic:2

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in activation of a cryptic donor splice site and introduces a premature termination codon (PMID: 27019227). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that this variant alters POLA1 gene expression (PMID: 27019227). ClinVar contains an entry for this variant (Variation ID: 224980). This variant has been observed in individuals with X-linked reticulate pigmentary disorder (PMID: 27019227). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change falls in intron 13 of the POLA1 gene. It does not directly change the encoded amino acid sequence of the POLA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in POLA1 cause disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	22
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.86		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312979; hg19: chrX-24744696;