X-24693982-C-T

Variant names:

• chrX-24693982-C-T
• rs760997065
• NM_001330360.2:c.21C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001330360.2(POLA1):​c.21C>T​(p.Asp7Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000537 in 1,192,825 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.000047 (0 hom. 21 hem.)
• Consequence: POLA1 NM_001330360.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.42
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-24693982-C-T is Benign according to our data. Variant chrX-24693982-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1590307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000115 (13/113296) while in subpopulation NFE AF = 0.000225 (12/53402). AF 95% confidence interval is 0.000129. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

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.21C>T	p.Asp7Asp	synonymous	Exon 1 of 37	NP_001317289.1	A6NMQ1
	POLA1	NM_001440806.1		c.21C>T	p.Asp7Asp	synonymous	Exon 1 of 38	NP_001427735.1
	POLA1	NM_016937.4		c.21C>T	p.Asp7Asp	synonymous	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.21C>T	p.Asp7Asp	synonymous	Exon 1 of 37	ENSP00000368358.3	A6NMQ1
	POLA1	ENST00000379059.7	TSL:1	c.21C>T	p.Asp7Asp	synonymous	Exon 1 of 37	ENSP00000368349.3	P09884
	POLA1	ENST00000933044.1		c.21C>T	p.Asp7Asp	synonymous	Exon 1 of 38	ENSP00000603103.1

Frequencies

GnomAD3 genomes AF: 0.000115 AC: 13 AN: 113296 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000923

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: 0.000225

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000887 AC: 13 AN: 146519 AF XY: 0.0000225

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: 0.000154

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 51 AN: 1079529 Hom.: 0 Cov.: 29 AF XY: 0.0000598 AC XY: 21 AN XY: 351105

African (AFR) AF: 0.0000774 AC: 2 AN: 25829

American (AMR) AF: 0.00 AC: 0 AN: 32949

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19052

East Asian (EAS) AF: 0.00 AC: 0 AN: 28985

South Asian (SAS) AF: 0.00 AC: 0 AN: 51529

European-Finnish (FIN) AF: 0.000128 AC: 5 AN: 39126

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4109

European-Non Finnish (NFE) AF: 0.0000480 AC: 40 AN: 832588

Other (OTH) AF: 0.0000661 AC: 3 AN: 45362

GnomAD4 genome AF: 0.000115 AC: 13 AN: 113296 Hom.: 0 Cov.: 24 AF XY: 0.0000847 AC XY: 3 AN XY: 35432

African (AFR) AF: 0.00 AC: 0 AN: 31298

American (AMR) AF: 0.0000923 AC: 1 AN: 10837

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2662

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6251

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000225 AC: 12 AN: 53402

Other (OTH) AF: 0.00 AC: 0 AN: 1535

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000132

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.69
DANN	Benign	0.89
PhyloP100		-3.4
PromoterAI		0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs760997065; hg19: chrX-24712099;