3-14145808-C-T

Variant names:

• chr3-14145808-C-T
• rs377250919
• NM_004628.5:c.*133G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004628.5(XPC):​c.*133G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,145,242 control chromosomes in the GnomAD database, including 17 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 0.00054 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (16 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.294
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-14145808-C-T is Benign according to our data. Variant chr3-14145808-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 343559.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000538 (82/152288) while in subpopulation SAS AF = 0.0158 (76/4822). AF 95% confidence interval is 0.0129. There are 1 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 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.*133G>A		3_prime_UTR	Exon 16 of 16	NP_004619.3
	XPC	NM_001354727.2		c.*133G>A		3_prime_UTR	Exon 16 of 16	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.*133G>A		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.*133G>A		3_prime_UTR	Exon 16 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*2409G>A		non_coding_transcript_exon	Exon 15 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000476581.6	TSL:1	n.*2409G>A		3_prime_UTR	Exon 15 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00224 AC: 346 AN: 154570 AF XY: 0.00294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000310

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.00107 AC: 1063 AN: 992954 Hom.: 16 Cov.: 13 AF XY: 0.00154 AC XY: 781 AN XY: 505844

African (AFR) AF: 0.00 AC: 0 AN: 23508

American (AMR) AF: 0.0000286 AC: 1 AN: 34974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21878

East Asian (EAS) AF: 0.000144 AC: 5 AN: 34638

South Asian (SAS) AF: 0.0140 AC: 1001 AN: 71408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39674

Middle Eastern (MID) AF: 0.000306 AC: 1 AN: 3268

European-Non Finnish (NFE) AF: 0.0000167 AC: 12 AN: 718976

Other (OTH) AF: 0.000963 AC: 43 AN: 44630

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

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

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5158

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4822

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (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	-0.87
CADD	Benign	1.8
DANN	Benign	0.55
PhyloP100		-0.29
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: rs377250919; hg19: chr3-14187308;