NM_004628.5:c.*192T>C

Variant names:

• chr3-14145749-A-G
• rs3731178
• NM_004628.5:c.*192T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004628.5(XPC):​c.*192T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 738,870 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (13 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.301
• Publications: 0 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]

ENSG00000268279 (HGNC:):

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-14145749-A-G is Benign according to our data. Variant chr3-14145749-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 343558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1527/152280) while in subpopulation AFR AF = 0.0345 (1435/41538). AF 95% confidence interval is 0.0331. There are 28 homozygotes in GnomAd4. There are 727 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

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.*192T>C		3_prime_UTR	Exon 16 of 16	NP_004619.3
	XPC	NM_001354727.2		c.*192T>C		3_prime_UTR	Exon 16 of 16	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.*192T>C		3_prime_UTR	Exon 16 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.*192T>C		3_prime_UTR	Exon 16 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*2468T>C		non_coding_transcript_exon	Exon 15 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000476581.6	TSL:1	n.*2468T>C		3_prime_UTR	Exon 15 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1528 AN: 152162 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00228 AC: 308 AN: 134806 AF XY: 0.00190

Gnomad AFR exome AF: 0.0379

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000572

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.00128 AC: 752 AN: 586590 Hom.: 13 Cov.: 6 AF XY: 0.00106 AC XY: 335 AN XY: 315364

African (AFR) AF: 0.0363 AC: 595 AN: 16396

American (AMR) AF: 0.00196 AC: 68 AN: 34738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20190

East Asian (EAS) AF: 0.00 AC: 0 AN: 32218

South Asian (SAS) AF: 0.0000639 AC: 4 AN: 62640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33700

Middle Eastern (MID) AF: 0.000792 AC: 2 AN: 2524

European-Non Finnish (NFE) AF: 0.0000284 AC: 10 AN: 352468

Other (OTH) AF: 0.00230 AC: 73 AN: 31716

GnomAD4 genome AF: 0.0100 AC: 1527 AN: 152280 Hom.: 28 Cov.: 32 AF XY: 0.00976 AC XY: 727 AN XY: 74456

African (AFR) AF: 0.0345 AC: 1435 AN: 41538

American (AMR) AF: 0.00477 AC: 73 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00443 Hom.: 9

Bravo AF: 0.0118

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	not provided (1)
-	-	1	Xeroderma pigmentosum (1)
-	-	1	Xeroderma pigmentosum, group C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.4
DANN	Benign	0.64
PhyloP100		-0.30
Mutation Taster		=100/0	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: rs3731178; hg19: chr3-14187249;