X-24693978-G-A

Variant names:

• chrX-24693978-G-A
• rs775792719
• NM_001330360.2:c.17G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001330360.2(POLA1):​c.17G>A​(p.Gly6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000838 in 1,193,917 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. G6S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000083 (0 hom. 4 hem.)
• Consequence: POLA1 NM_001330360.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07081717).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000833 (9/1080484) while in subpopulation SAS AF = 0.000174 (9/51601). AF 95% confidence interval is 0.0000907. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLA1	NM_001330360.2	c.17G>A	p.Gly6Asp	missense_variant	Exon 1 of 37	ENST00000379068.8	NP_001317289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLA1	ENST00000379068.8	c.17G>A	p.Gly6Asp	missense_variant	Exon 1 of 37	5	NM_001330360.2	ENSP00000368358.3

Frequencies

GnomAD3 genomes AF: 0.00000882 AC: 1 AN: 113433 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000355

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000339 AC: 5 AN: 147300 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000833 AC: 9 AN: 1080484 Hom.: 0 Cov.: 29 AF XY: 0.0000114 AC XY: 4 AN XY: 351822

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 25838

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 33078

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19075

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 29033

Gnomad4 SAS exome AF: 0.000174 AC: 9 AN: 51601

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 39169

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 833184

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 45393

GnomAD4 genome AF: 0.00000882 AC: 1 AN: 113433 Hom.: 0 Cov.: 24 AF XY: 0.0000281 AC XY: 1 AN XY: 35559

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000355 AC: 0.00035461 AN: 0.00035461

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000253 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with POLA1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 6 of the POLA1 protein (p.Gly6Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.17	.;.;T
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.62	N;.;N
REVEL	Benign	0.080
Sift	Benign	0.040	D;.;D
Sift4G	Benign	0.86	T;T;T
Polyphen		0.041	B;.;B
Vest4		0.14
MutPred		0.32		Loss of relative solvent accessibility (P = 0.0981);Loss of relative solvent accessibility (P = 0.0981);Loss of relative solvent accessibility (P = 0.0981);
MVP		0.34
MPC		0.63
ClinPred		0.042	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.089
gMVP		0.059
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs775792719; hg19: chrX-24712095;