rs2228002

chr3-14170550-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004628.5(XPC):c.300G>A(p.Arg100=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,608,880 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (150 hom.)
• Consequence: XPC NM_004628.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.006728
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.410

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-14170550-C-T is Benign according to our data. Variant chr3-14170550-C-T is described in ClinVar as [Benign]. Clinvar id is 135476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14170550-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.300G>A	p.Arg100=	splice_region_variant, synonymous_variant	3/16	ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.300G>A	p.Arg100=	splice_region_variant, synonymous_variant	3/16	1	NM_004628.5	P1
XPC	ENST00000476581.6	c.300G>A	p.Arg100=	splice_region_variant, synonymous_variant, NMD_transcript_variant	3/15	1
XPC	ENST00000511155.1	c.282G>A	p.Arg94=	splice_region_variant, synonymous_variant	3/4	4
XPC	ENST00000452172.1	n.65G>A		non_coding_transcript_exon_variant	1/5	4

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3341 AN: 152120 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00550 AC: 1353 AN: 245992 Hom.: 55 AF XY: 0.00392 AC XY: 524 AN XY: 133550

Gnomad AFR exome AF: 0.0790

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00228 AC: 3317 AN: 1456642 Hom.: 150 Cov.: 29 AF XY: 0.00192 AC XY: 1392 AN XY: 724398

Gnomad4 AFR exome AF: 0.0825

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.0219 AC: 3340 AN: 152238 Hom.: 120 Cov.: 32 AF XY: 0.0214 AC XY: 1595 AN XY: 74442

Gnomad4 AFR AF: 0.0755

Gnomad4 AMR AF: 0.00974

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00451 Hom.: 34

Bravo AF: 0.0250

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2019	Variant summary: XPC c.300G>A (p.Arg100Arg) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0074 in 277384 control chromosomes, predominantly at a frequency of 0.079 within the African or African-American subpopulation in the gnomAD database, including 81 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 56 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma pigmentosum phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Xeroderma pigmentosum, group C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Xeroderma pigmentosum group A Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	12
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0067
dbscSNV1_RF	Benign	0.044
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2228002; hg19: chr3-14212050; COSMIC: COSV104532508; COSMIC: COSV104532508;