X-24699475-A-AATG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001330360.2(POLA1):c.95_96insTGA(p.Lys32delinsAsnGlu) variant causes a protein altering change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K32K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: POLA1 NM_001330360.2 protein_altering
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLA1	NM_001330360.2	c.95_96insTGA	p.Lys32delinsAsnGlu	protein_altering_variant	2/37	ENST00000379068.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLA1	ENST00000379068.8	c.95_96insTGA	p.Lys32delinsAsnGlu	protein_altering_variant	2/37	5	NM_001330360.2	A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 11, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with POLA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.77_78insTGA, is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the POLA1 protein (p.Lys26delinsAsnGlu). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-24717592;