rs2733534

Variant names:

• chr3-14147262-G-C
• rs2733534
• NM_004628.5:c.2604+28C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-14147262-G-C
• chr3-14147262-G-A

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.2604+28C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,588,642 control chromosomes in the GnomAD database, including 168,371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13684 hom., cov: 32)
  • Exomes 𝑓: 0.46 (154687 hom.)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0280
• Publications: 16 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: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-14147262-G-C is Benign according to our data. Variant chr3-14147262-G-C is described in ClinVar as Benign. ClinVar VariationId is 259470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.468 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.2604+28C>G		intron	N/A	NP_004619.3
	XPC	NM_001354727.2		c.2598+28C>G		intron	N/A	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.2586+28C>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.2604+28C>G		intron	N/A	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*2057+28C>G		intron	N/A	ENSP00000424548.1	Q01831-3
	ENSG00000268279	ENST00000608606.1	TSL:5	n.*199-689G>C		intron	N/A	ENSP00000476275.1	V9GY05

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62963 AN: 151908 Hom.: 13676 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.444

GnomAD2 exomes AF: 0.411 AC: 87089 AN: 212032 AF XY: 0.411

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.0412

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.456 AC: 655326 AN: 1436616 Hom.: 154687 Cov.: 31 AF XY: 0.454 AC XY: 323158 AN XY: 712294

African (AFR) AF: 0.354 AC: 11678 AN: 32958

American (AMR) AF: 0.424 AC: 17193 AN: 40572

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 10944 AN: 25656

East Asian (EAS) AF: 0.0393 AC: 1528 AN: 38844

South Asian (SAS) AF: 0.390 AC: 32051 AN: 82100

European-Finnish (FIN) AF: 0.461 AC: 24008 AN: 52056

Middle Eastern (MID) AF: 0.353 AC: 2023 AN: 5738

European-Non Finnish (NFE) AF: 0.483 AC: 530465 AN: 1099138

Other (OTH) AF: 0.427 AC: 25436 AN: 59554

GnomAD4 genome AF: 0.414 AC: 63012 AN: 152026 Hom.: 13684 Cov.: 32 AF XY: 0.412 AC XY: 30617 AN XY: 74342

African (AFR) AF: 0.352 AC: 14598 AN: 41432

American (AMR) AF: 0.412 AC: 6295 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1508 AN: 3468

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5176

South Asian (SAS) AF: 0.388 AC: 1870 AN: 4824

European-Finnish (FIN) AF: 0.461 AC: 4880 AN: 10578

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32129 AN: 67964

Other (OTH) AF: 0.440 AC: 929 AN: 2112

Alfa AF: 0.437 Hom.: 2736

Bravo AF: 0.409

Asia WGS AF: 0.250 AC: 867 AN: 3478

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	-0.81
CADD	Benign	2.5
DANN	Benign	0.71
PhyloP100		0.028
Mutation Taster		=100/0	polymorphism (auto)

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: rs2733534; hg19: chr3-14188762; COSMIC: COSV53203693; COSMIC: COSV53203693;