3-14164841-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004628.5(XPC):c.872C>G(p.Ser291Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00179 in 1,613,562 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (17 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 5.27

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01001206).
• BP6: Variant 3-14164841-G-C is Benign according to our data. Variant chr3-14164841-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135481.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, not_provided=1, Uncertain_significance=1}. Variant chr3-14164841-G-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5	c.872C>G	p.Ser291Cys	missense_variant	7/16	ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12	c.872C>G	p.Ser291Cys	missense_variant	7/16	1	NM_004628.5	P1
XPC-AS1	ENST00000627116.2	n.457-1035G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152168 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00322 AC: 801 AN: 248774 Hom.: 7 AF XY: 0.00310 AC XY: 418 AN XY: 134968

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.000931

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.00381

GnomAD4 exome AF: 0.00168 AC: 2452 AN: 1461276 Hom.: 17 Cov.: 30 AF XY: 0.00168 AC XY: 1223 AN XY: 726894

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000828

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0269

Gnomad4 NFE exome AF: 0.000729

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00290 AC: 441 AN: 152286 Hom.: 8 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74452

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000842

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00155 AC: 6

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.00281 AC: 340

EpiCase AF: 0.000982

EpiControl AF: 0.000653

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Xeroderma pigmentosum, group C Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.22
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.32
MVP		0.38
MPC		0.55
ClinPred		0.016	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.44

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: rs184879571; hg19: chr3-14206341; COSMIC: COSV99542159; COSMIC: COSV99542159;