chr3-14152389-C-T

Variant names:

• chr3-14152389-C-T
• rs2227998
• NM_004628.5:c.2061G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004628.5(XPC):​c.2061G>A​(p.Arg687Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,611,184 control chromosomes in the GnomAD database, including 56,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5328 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51627 hom.)
• Consequence: XPC NM_004628.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.36
• Publications: 29 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.058).
• BP6: Variant 3-14152389-C-T is Benign according to our data. Variant chr3-14152389-C-T is described in ClinVar as Benign. ClinVar VariationId is 135469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 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.2061G>A	p.Arg687Arg	synonymous	Exon 11 of 16	NP_004619.3
	XPC	NM_001354727.2		c.2055G>A	p.Arg685Arg	synonymous	Exon 11 of 16	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.2043G>A	p.Arg681Arg	synonymous	Exon 11 of 16	NP_001341658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.2061G>A	p.Arg687Arg	synonymous	Exon 11 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*1514G>A		non_coding_transcript_exon	Exon 10 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000476581.6	TSL:1	n.*1514G>A		3_prime_UTR	Exon 10 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39500 AN: 151998 Hom.: 5321 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.259

GnomAD2 exomes AF: 0.253 AC: 62068 AN: 245744 AF XY: 0.251

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.0394

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.261 AC: 381438 AN: 1459068 Hom.: 51627 Cov.: 33 AF XY: 0.261 AC XY: 189298 AN XY: 725600

African (AFR) AF: 0.309 AC: 10336 AN: 33410

American (AMR) AF: 0.310 AC: 13759 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5943 AN: 26094

East Asian (EAS) AF: 0.0387 AC: 1533 AN: 39644

South Asian (SAS) AF: 0.286 AC: 24527 AN: 85770

European-Finnish (FIN) AF: 0.228 AC: 12150 AN: 53260

Middle Eastern (MID) AF: 0.207 AC: 1190 AN: 5760

European-Non Finnish (NFE) AF: 0.267 AC: 296877 AN: 1110502

Other (OTH) AF: 0.251 AC: 15123 AN: 60304

GnomAD4 genome AF: 0.260 AC: 39546 AN: 152116 Hom.: 5328 Cov.: 32 AF XY: 0.258 AC XY: 19193 AN XY: 74374

African (AFR) AF: 0.301 AC: 12474 AN: 41484

American (AMR) AF: 0.258 AC: 3944 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 790 AN: 3472

East Asian (EAS) AF: 0.0417 AC: 216 AN: 5182

South Asian (SAS) AF: 0.291 AC: 1403 AN: 4818

European-Finnish (FIN) AF: 0.220 AC: 2329 AN: 10596

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17635 AN: 67964

Other (OTH) AF: 0.257 AC: 543 AN: 2110

Alfa AF: 0.265 Hom.: 3746

Bravo AF: 0.265

Asia WGS AF: 0.210 AC: 728 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2227998; hg19: chr3-14193889; COSMIC: COSV53204988; COSMIC: COSV53204988;