3-14165489-G-C

Variant names:

• chr3-14165489-G-C
• rs552222088
• NM_004628.5:c.718C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004628.5(XPC):​c.718C>G​(p.Arg240Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,194 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R240C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.718C>G	p.Arg240Gly	missense	Exon 6 of 16	NP_004619.3
	XPC	NM_001354727.2		c.718C>G	p.Arg240Gly	missense	Exon 6 of 16	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.700C>G	p.Arg234Gly	missense	Exon 6 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.718C>G	p.Arg240Gly	missense	Exon 6 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*171C>G		non_coding_transcript_exon	Exon 5 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000476581.6	TSL:1	n.*171C>G		3_prime_UTR	Exon 5 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238244 AF XY: 0.00000777

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455194 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723046

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 43748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108836

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.2
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.15
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.022	D
Polyphen		0.42	B
Vest4		0.44
MutPred		0.73		Loss of stability (P = 0.0339)
MVP		0.21
MPC		0.20
ClinPred		0.57	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.29
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs552222088; hg19: chr3-14206989;