rs587778758

Variant names:

• chr3-14156447-A-G
• rs587778758
• NM_004628.5:c.1921T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004628.5(XPC):​c.1921T>C​(p.Tyr641His) variant causes a missense change. The variant allele was found at a frequency of 0.0000294 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: XPC NM_004628.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.95
• Publications: 4 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

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.1921T>C	p.Tyr641His	missense	Exon 10 of 16	NP_004619.3
	XPC	NM_001354729.2		c.1903T>C	p.Tyr635His	missense	Exon 10 of 16	NP_001341658.1
	XPC	NM_001354730.2		c.1675T>C	p.Tyr559His	missense	Exon 10 of 16	NP_001341659.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.1921T>C	p.Tyr641His	missense	Exon 10 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*1374T>C		non_coding_transcript_exon	Exon 9 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000476581.6	TSL:1	n.*1374T>C		3_prime_UTR	Exon 9 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249248 AF XY: 0.00000740

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: 0.0000464

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461692 Hom.: 0 Cov.: 29 AF XY: 0.0000303 AC XY: 22 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.095	T
Polyphen		1.0	D
Vest4		0.81
MVP		0.43
MPC		0.64
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.68
gMVP		0.84
Mutation Taster		=52/48	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: rs587778758; hg19: chr3-14197947;