rs2607775

Positions:

• chr3-14178595-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004628.5(XPC):​c.-27G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,612,026 control chromosomes in the GnomAD database, including 172,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14100 hom., cov: 34)
  • Exomes 𝑓: 0.46 (158875 hom.)
• Consequence: XPC NM_004628.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.90

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-14178595-C-G is Benign according to our data. Variant chr3-14178595-C-G is described in ClinVar as [Benign]. Clinvar id is 259465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPC	NM_004628.5	c.-27G>C		5_prime_UTR_variant	1/16	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.-27G>C		5_prime_UTR_variant	1/16	1	NM_004628.5	ENSP00000285021.8
XPC	ENST00000476581.6	n.-27G>C		non_coding_transcript_exon_variant	1/15	1		ENSP00000424548.1
XPC	ENST00000476581.6	n.-27G>C		5_prime_UTR_variant	1/15	1		ENSP00000424548.1
XPC	ENST00000511155.1	c.-27G>C		5_prime_UTR_variant	1/4	4		ENSP00000423867.1

Frequencies

GnomAD3 genomes AF: 0.421 AC: 64108 AN: 152102 Hom.: 14088 Cov.: 34

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.447

GnomAD3 exomes AF: 0.415 AC: 102197 AN: 246200 Hom.: 22923 AF XY: 0.416 AC XY: 55820 AN XY: 134194

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.0409

Gnomad SAS exome AF: 0.394

Gnomad FIN exome AF: 0.461

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.458 AC: 669200 AN: 1459806 Hom.: 158875 Cov.: 45 AF XY: 0.456 AC XY: 331040 AN XY: 726302

Gnomad4 AFR exome AF: 0.375

Gnomad4 AMR exome AF: 0.428

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.0396

Gnomad4 SAS exome AF: 0.391

Gnomad4 FIN exome AF: 0.461

Gnomad4 NFE exome AF: 0.485

Gnomad4 OTH exome AF: 0.431

GnomAD4 genome AF: 0.421 AC: 64159 AN: 152220 Hom.: 14100 Cov.: 34 AF XY: 0.419 AC XY: 31190 AN XY: 74434

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.0422

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.475

Gnomad4 OTH AF: 0.443

Alfa AF: 0.442 Hom.: 2780

Bravo AF: 0.417

Asia WGS AF: 0.253 AC: 881 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.75
CADD	Benign	1.9
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs2607775; hg19: chr3-14220095; COSMIC: COSV53204236;