rs2229089

chr3-14173024-G-Achr3-14173024-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004628.5(XPC):c.142C>T(p.Leu48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,606,840 control chromosomes in the GnomAD database, including 738 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (48 hom., cov: 32)
  • Exomes 𝑓: 0.028 (690 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.240

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023067892).
• BP6: Variant 3-14173024-G-A is Benign according to our data. Variant chr3-14173024-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-14173024-G-A is described in Lovd as [Benign]. Variant chr3-14173024-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3225/152266) while in subpopulation NFE AF= 0.0287 (1949/68008). AF 95% confidence interval is 0.0276. There are 48 homozygotes in gnomad4. There are 1657 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.142C>T	p.Leu48Phe	missense_variant	2/16	ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.142C>T	p.Leu48Phe	missense_variant	2/16	1	NM_004628.5	P1
XPC	ENST00000476581.6	c.142C>T	p.Leu48Phe	missense_variant, NMD_transcript_variant	2/15	1
XPC	ENST00000511155.1	c.124C>T	p.Leu42Phe	missense_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3225 AN: 152148 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0215 AC: 5095 AN: 236852 Hom.: 94 AF XY: 0.0224 AC XY: 2882 AN XY: 128600

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.00894

Gnomad ASJ exome AF: 0.00537

Gnomad EAS exome AF: 0.000175

Gnomad SAS exome AF: 0.0140

Gnomad FIN exome AF: 0.0564

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0278 AC: 40465 AN: 1454574 Hom.: 690 Cov.: 31 AF XY: 0.0276 AC XY: 19937 AN XY: 723250

Gnomad4 AFR exome AF: 0.00366

Gnomad4 AMR exome AF: 0.00956

Gnomad4 ASJ exome AF: 0.00552

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0140

Gnomad4 FIN exome AF: 0.0532

Gnomad4 NFE exome AF: 0.0309

Gnomad4 OTH exome AF: 0.0235

GnomAD4 genome AF: 0.0212 AC: 3225 AN: 152266 Hom.: 48 Cov.: 32 AF XY: 0.0223 AC XY: 1657 AN XY: 74444

Gnomad4 AFR AF: 0.00488

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0156

Gnomad4 FIN AF: 0.0586

Gnomad4 NFE AF: 0.0287

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0248 Hom.: 97

Bravo AF: 0.0175

TwinsUK AF: 0.0329 AC: 122

ALSPAC AF: 0.0327 AC: 126

ESP6500AA AF: 0.00506 AC: 19

ESP6500EA AF: 0.0287 AC: 236

ExAC AF: 0.0201 AC: 2424

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2019	This variant is associated with the following publications: (PMID: 28146470) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Xeroderma pigmentosum, group C Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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. -

Xeroderma pigmentosum group A Benign:1

Likely 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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.6
Dann	Benign	0.79
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.093
Sift	Benign	0.73	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0050	B;.
Vest4		0.026
MPC		0.22
ClinPred		0.00073	T
GERP RS		1.0
Varity_R		0.019
gMVP		0.030

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: rs2229089; hg19: chr3-14214524; COSMIC: COSV53208173; COSMIC: COSV53208173;