X-24714619-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001330360.2(POLA1):​c.412A>T​(p.Asn138Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000922 in 1,085,027 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N138D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: POLA1 NM_001330360.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

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>T	p.Asn138Tyr	missense	Exon 5 of 37	NP_001317289.1	A6NMQ1
	POLA1	NM_001440806.1		c.412A>T	p.Asn138Tyr	missense	Exon 5 of 38	NP_001427735.1
	POLA1	NM_016937.4		c.394A>T	p.Asn132Tyr	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>T	p.Asn138Tyr	missense	Exon 5 of 37	ENSP00000368358.3	A6NMQ1
	POLA1	ENST00000379059.7	TSL:1	c.394A>T	p.Asn132Tyr	missense	Exon 5 of 37	ENSP00000368349.3	P09884
	POLA1	ENST00000933044.1		c.394A>T	p.Asn132Tyr	missense	Exon 5 of 38	ENSP00000603103.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1085027 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 351171

African (AFR) AF: 0.00 AC: 0 AN: 26209

American (AMR) AF: 0.00 AC: 0 AN: 34800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19211

East Asian (EAS) AF: 0.00 AC: 0 AN: 30121

South Asian (SAS) AF: 0.00 AC: 0 AN: 52526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40351

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 832070

Other (OTH) AF: 0.00 AC: 0 AN: 45695

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.27
Sift	Benign	0.031	D
Sift4G	Uncertain	0.055	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.36		Loss of disorder (P = 0.0236)
MVP		0.77
MPC		0.75
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.35
Mutation Taster		=79/21	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;