rs2733532

Variant names:

• chr3-14146199-T-C
• rs2733532
• NM_004628.5:c.2605-40A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-14146199-T-C
• chr3-14146199-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004628.5(XPC):​c.2605-40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,548,762 control chromosomes in the GnomAD database, including 297,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.66 (32936 hom., cov: 27)
  • Exomes 𝑓: 0.61 (264361 hom.)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.605
• Publications: 20 publications found

Genes affected

XPC (HGNC:12816): (XPC complex subunit, DNA damage recognition and repair factor) The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

ENSG00000268279 (HGNC:):

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-14146199-T-C is Benign according to our data. Variant chr3-14146199-T-C is described in ClinVar as Benign. ClinVar VariationId is 259471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004628.5. 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
	XPC	NM_004628.5	MANE Select	c.2605-40A>G		intron	N/A	NP_004619.3
	XPC	NM_001354727.2		c.2599-40A>G		intron	N/A	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.2587-40A>G		intron	N/A	NP_001341658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.2605-40A>G		intron	N/A	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*2058-40A>G		intron	N/A	ENSP00000424548.1	Q01831-3
	ENSG00000268279	ENST00000608606.1	TSL:5	n.*198+516T>C		intron	N/A	ENSP00000476275.1	V9GY05

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99151 AN: 151088 Hom.: 32886 Cov.: 27

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.648

GnomAD2 exomes AF: 0.640 AC: 110034 AN: 172046 AF XY: 0.635

Gnomad AFR exome AF: 0.751

Gnomad AMR exome AF: 0.709

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.648

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.600

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.613 AC: 856984 AN: 1397556 Hom.: 264361 Cov.: 27 AF XY: 0.612 AC XY: 423760 AN XY: 692150

African (AFR) AF: 0.752 AC: 24144 AN: 32126

American (AMR) AF: 0.705 AC: 26426 AN: 37502

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 13375 AN: 25260

East Asian (EAS) AF: 0.623 AC: 23174 AN: 37220

South Asian (SAS) AF: 0.647 AC: 52235 AN: 80686

European-Finnish (FIN) AF: 0.692 AC: 29363 AN: 42418

Middle Eastern (MID) AF: 0.461 AC: 2427 AN: 5268

European-Non Finnish (NFE) AF: 0.603 AC: 650433 AN: 1078736

Other (OTH) AF: 0.607 AC: 35407 AN: 58340

GnomAD4 genome AF: 0.657 AC: 99276 AN: 151206 Hom.: 32936 Cov.: 27 AF XY: 0.662 AC XY: 48824 AN XY: 73804

African (AFR) AF: 0.746 AC: 30713 AN: 41174

American (AMR) AF: 0.676 AC: 10297 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1849 AN: 3466

East Asian (EAS) AF: 0.642 AC: 3259 AN: 5078

South Asian (SAS) AF: 0.660 AC: 3127 AN: 4736

European-Finnish (FIN) AF: 0.702 AC: 7381 AN: 10518

Middle Eastern (MID) AF: 0.490 AC: 143 AN: 292

European-Non Finnish (NFE) AF: 0.598 AC: 40506 AN: 67714

Other (OTH) AF: 0.651 AC: 1363 AN: 2094

Alfa AF: 0.614 Hom.: 7227

Bravo AF: 0.659

Asia WGS AF: 0.684 AC: 2376 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Xeroderma pigmentosum, group C (2)
-	-	1	not specified (1)
-	-	1	Xeroderma pigmentosum group A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.9
DANN	Benign	0.73
PhyloP100		-0.60
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2733532; hg19: chr3-14187699; COSMIC: COSV53204549; COSMIC: COSV53204549;