NM_001330360.2:c.13C>T

Variant names:

• chrX-24693974-C-T
• NM_001330360.2:c.13C>T

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.13C>T​(p.His5Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: POLA1 NM_001330360.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.575
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13896763).

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.13C>T	p.His5Tyr	missense	Exon 1 of 37	NP_001317289.1	A6NMQ1
	POLA1	NM_001440806.1		c.13C>T	p.His5Tyr	missense	Exon 1 of 38	NP_001427735.1
	POLA1	NM_016937.4		c.13C>T	p.His5Tyr	missense	Exon 1 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.13C>T	p.His5Tyr	missense	Exon 1 of 37	ENSP00000368358.3	A6NMQ1
	POLA1	ENST00000379059.7	TSL:1	c.13C>T	p.His5Tyr	missense	Exon 1 of 37	ENSP00000368349.3	P09884
	POLA1	ENST00000933044.1		c.13C>T	p.His5Tyr	missense	Exon 1 of 38	ENSP00000603103.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1080650 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 351884

African (AFR) AF: 0.00 AC: 0 AN: 25877

American (AMR) AF: 0.00 AC: 0 AN: 33091

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19090

East Asian (EAS) AF: 0.00 AC: 0 AN: 29055

South Asian (SAS) AF: 0.00 AC: 0 AN: 51628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39183

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833224

Other (OTH) AF: 0.00 AC: 0 AN: 45390

GnomAD4 genome Cov.: 25

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	0.085
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.57
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.010
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.21	T
Polyphen		0.82	P
Vest4		0.14
MutPred		0.41		Gain of catalytic residue at H5 (P = 0.0446)
MVP		0.17
MPC		0.92
ClinPred		0.68	D
GERP RS		2.7
PromoterAI		0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.17
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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

hg19: chrX-24712091;