rs772554190

Variant names:

• chrX-24699473-A-G
• rs772554190
• NM_001330360.2:c.92A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330360.2(POLA1):​c.92A>G​(p.Lys31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,187,686 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: POLA1 NM_001330360.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80
• Publications: 2 publications found

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]

POLA1 Gene-Disease associations (from GenCC):

• X-linked intellectual disability, van Esch type

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked reticulate pigmentary disorder

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1809819).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330360.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLA1	NM_001330360.2	MANE Select	c.92A>G	p.Lys31Arg	missense	Exon 2 of 37	NP_001317289.1	A6NMQ1
	POLA1	NM_001440806.1		c.92A>G	p.Lys31Arg	missense	Exon 2 of 38	NP_001427735.1
	POLA1	NM_016937.4		c.74A>G	p.Lys25Arg	missense	Exon 2 of 37	NP_058633.2	P09884

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLA1	ENST00000379068.8	TSL:5 MANE Select	c.92A>G	p.Lys31Arg	missense	Exon 2 of 37	ENSP00000368358.3	A6NMQ1
	POLA1	ENST00000379059.7	TSL:1	c.74A>G	p.Lys25Arg	missense	Exon 2 of 37	ENSP00000368349.3	P09884
	POLA1	ENST00000933044.1		c.74A>G	p.Lys25Arg	missense	Exon 2 of 38	ENSP00000603103.1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111230 Hom.: 0 Cov.: 22

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000632 AC: 1 AN: 158131 AF XY: 0.00

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: 0.0000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1076456 Hom.: 0 Cov.: 26 AF XY: 0.00000289 AC XY: 1 AN XY: 346044

African (AFR) AF: 0.00 AC: 0 AN: 25995

American (AMR) AF: 0.00 AC: 0 AN: 34132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19047

East Asian (EAS) AF: 0.00 AC: 0 AN: 29739

South Asian (SAS) AF: 0.00 AC: 0 AN: 50376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39661

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 828347

Other (OTH) AF: 0.00 AC: 0 AN: 45097

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111230 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33416

African (AFR) AF: 0.00 AC: 0 AN: 30518

American (AMR) AF: 0.00 AC: 0 AN: 10398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53123

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.36	T
Sift4G	Benign	0.56	T
Polyphen		0.022	B
Vest4		0.11
MutPred		0.23		Gain of helix (P = 0.132)
MVP		0.87
MPC		0.97
ClinPred		0.61	D
GERP RS		5.0
Varity_R		0.38
gMVP		0.086
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs772554190; hg19: chrX-24717590;