3-14173024-G-T

Variant names:

• chr3-14173024-G-T
• rs2229089
• NM_004628.5:c.142C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004628.5(XPC):​c.142C>A​(p.Leu48Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. L48F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.240
• Publications: 18 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 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health, Genomics England PanelApp
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042086124).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	NM_004628.5	MANE Select	c.142C>A	p.Leu48Ile	missense	Exon 2 of 16	NP_004619.3
	XPC	NM_001354727.2		c.142C>A	p.Leu48Ile	missense	Exon 2 of 16	NP_001341656.1
	XPC	NM_001354729.2		c.124C>A	p.Leu42Ile	missense	Exon 2 of 16	NP_001341658.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.142C>A	p.Leu48Ile	missense	Exon 2 of 16	ENSP00000285021.8
	XPC	ENST00000476581.6	TSL:1	n.142C>A		non_coding_transcript_exon	Exon 2 of 15	ENSP00000424548.1
	XPC	ENST00000850575.1		c.142C>A	p.Leu48Ile	missense	Exon 2 of 16	ENSP00000520865.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 203

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.1
DANN	Benign	0.75
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.24
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.070
Sift	Benign	0.41	T
Sift4G	Benign	0.42	T
Polyphen		0.27	B
Vest4		0.15
MutPred		0.23		Gain of glycosylation at S49 (P = 0.0044)
MVP		0.12
MPC		0.13
ClinPred		0.069	T
GERP RS		1.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.021
gMVP		0.024
Mutation Taster		=95/5	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: rs2229089; hg19: chr3-14214524;