X-24699428-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330360.2(POLA1):c.47T>C(p.Leu16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,046,361 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: POLA1 NM_001330360.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.683

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09990758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLA1	NM_001330360.2	c.47T>C	p.Leu16Pro	missense_variant	2/37	ENST00000379068.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLA1	ENST00000379068.8	c.47T>C	p.Leu16Pro	missense_variant	2/37	5	NM_001330360.2	A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000141 AC: 2 AN: 141893 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 38501

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000988

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000191 AC: 2 AN: 1046361 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 328275

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000686

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000828 AC: 1

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

GeneDx

Jun 06, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.94
Cadd	Benign	9.7
Dann	Benign	0.89
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.18	T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Benign	0.021
Sift	Benign	0.052	T;.;T
Sift4G	Benign	0.18	T;D;D
Polyphen		0.17	B;.;B
Vest4		0.096
MutPred		0.48		Loss of stability (P = 0.0105);.;.;
MVP		0.068
MPC		0.59
ClinPred		0.034	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746408076; hg19: chrX-24717545;