rs869312979

Positions:

• 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/exons	MANE	UniProt
POLA1	NM_001330360.2	c.1393-354A>G		intron_variant		ENST00000379068.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLA1	ENST00000379068.8	c.1393-354A>G		intron_variant		5	NM_001330360.2	A1

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 25, 2021	- -
Pathogenic, criteria provided, single submitter	literature only	SNPedia	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	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. 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). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -

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;