X-24714619-A-G

Variant names:

• chrX-24714619-A-G
• rs1555973963
• NM_001330360.2:c.412A>G

Variant summary

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

The NM_001330360.2(POLA1):​c.412A>G​(p.Asn138Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: POLA1 NM_001330360.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38
• Publications: 0 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 2 ACMG points.

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

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.412A>G	p.Asn138Asp	missense	Exon 5 of 37	NP_001317289.1	A6NMQ1
	POLA1	NM_001440806.1		c.412A>G	p.Asn138Asp	missense	Exon 5 of 38	NP_001427735.1
	POLA1	NM_016937.4		c.394A>G	p.Asn132Asp	missense	Exon 5 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.412A>G	p.Asn138Asp	missense	Exon 5 of 37	ENSP00000368358.3	A6NMQ1
	POLA1	ENST00000379059.7	TSL:1	c.394A>G	p.Asn132Asp	missense	Exon 5 of 37	ENSP00000368349.3	P09884
	POLA1	ENST00000933044.1		c.394A>G	p.Asn132Asp	missense	Exon 5 of 38	ENSP00000603103.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	X-linked reticulate pigmentary disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Benign	0.24	T
Sift4G	Benign	0.44	T
Polyphen		0.95	P
Vest4		0.57
MutPred		0.27		Loss of MoRF binding (P = 0.0509)
MVP		0.90
MPC		0.61
ClinPred		0.96	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.26
Mutation Taster		=78/22	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: rs1555973963; hg19: chrX-24732736;