rs2279017

Variant names:

• chr3-14148737-T-G
• rs2279017
• NM_004628.5:c.2251-6A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-14148737-T-G
• chr3-14148737-T-C

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.2251-6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,613,516 control chromosomes in the GnomAD database, including 304,401 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31584 hom., cov: 32)
  • Exomes 𝑓: 0.61 (272817 hom.)
• Consequence: XPC NM_004628.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004812
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0560
• Publications: 33 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]

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=-0.84).
• BP6: Variant 3-14148737-T-G is Benign according to our data. Variant chr3-14148737-T-G is described in ClinVar as Benign. ClinVar VariationId is 190214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 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.2251-6A>C		splice_region intron	N/A	NP_004619.3
	XPC	NM_001354727.2		c.2245-6A>C		splice_region intron	N/A	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.2233-6A>C		splice_region 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.2251-6A>C		splice_region intron	N/A	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*1704-6A>C		splice_region intron	N/A	ENSP00000424548.1	Q01831-3
	XPC	ENST00000850575.1		c.2245-6A>C		splice_region intron	N/A	ENSP00000520865.1	A0ABB0MVJ4

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97494 AN: 151914 Hom.: 31541 Cov.: 32

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.641

GnomAD2 exomes AF: 0.633 AC: 157405 AN: 248834 AF XY: 0.626

Gnomad AFR exome AF: 0.709

Gnomad AMR exome AF: 0.705

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.698

Gnomad NFE exome AF: 0.593

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.609 AC: 890414 AN: 1461484 Hom.: 272817 Cov.: 84 AF XY: 0.608 AC XY: 442169 AN XY: 726988

African (AFR) AF: 0.707 AC: 23672 AN: 33478

American (AMR) AF: 0.702 AC: 31390 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 13827 AN: 26136

East Asian (EAS) AF: 0.618 AC: 24513 AN: 39690

South Asian (SAS) AF: 0.646 AC: 55725 AN: 86256

European-Finnish (FIN) AF: 0.692 AC: 36973 AN: 53398

Middle Eastern (MID) AF: 0.455 AC: 2622 AN: 5764

European-Non Finnish (NFE) AF: 0.598 AC: 665291 AN: 1111696

Other (OTH) AF: 0.603 AC: 36401 AN: 60372

GnomAD4 genome AF: 0.642 AC: 97611 AN: 152032 Hom.: 31584 Cov.: 32 AF XY: 0.648 AC XY: 48128 AN XY: 74294

African (AFR) AF: 0.705 AC: 29223 AN: 41450

American (AMR) AF: 0.668 AC: 10211 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1848 AN: 3468

East Asian (EAS) AF: 0.637 AC: 3282 AN: 5150

South Asian (SAS) AF: 0.658 AC: 3172 AN: 4824

European-Finnish (FIN) AF: 0.700 AC: 7404 AN: 10576

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.594 AC: 40383 AN: 67962

Other (OTH) AF: 0.644 AC: 1362 AN: 2114

Alfa AF: 0.611 Hom.: 17013

Bravo AF: 0.642

Asia WGS AF: 0.677 AC: 2354 AN: 3478

EpiCase AF: 0.570

EpiControl AF: 0.573

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Xeroderma pigmentosum, group C (3)
-	-	2	not specified (2)
-	-	1	Xeroderma pigmentosum group A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.9
DANN	Benign	0.53
PhyloP100		0.056
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.046
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: rs2279017; hg19: chr3-14190237; COSMIC: COSV53203698; COSMIC: COSV53203698;