chr3-14145330-A-G

Variant names:

• chr3-14145330-A-G
• rs2470352
• NM_004628.5:c.*611T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004628.5(XPC):​c.*611T>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 0.00244 in 697,694 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (7 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.63
• Publications: 15 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00726 (1102/151796) while in subpopulation AFR AF = 0.0241 (997/41382). AF 95% confidence interval is 0.0229. There are 21 homozygotes in GnomAd4. There are 519 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 21 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.*611T>C		3_prime_UTR	Exon 16 of 16	NP_004619.3
	XPC	NM_001354727.2		c.*611T>C		3_prime_UTR	Exon 16 of 16	NP_001341656.1
	XPC	NM_001354729.2		c.*611T>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.*611T>C		3_prime_UTR	Exon 16 of 16	ENSP00000285021.8
	ENSG00000268279	ENST00000608606.1	TSL:5	n.244A>G		non_coding_transcript_exon	Exon 4 of 5	ENSP00000476275.1
	XPC	ENST00000850575.1		c.*611T>C		3_prime_UTR	Exon 16 of 16	ENSP00000520865.1

Frequencies

GnomAD3 genomes AF: 0.00723 AC: 1097 AN: 151678 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00385

GnomAD2 exomes AF: 0.00175 AC: 224 AN: 128366 AF XY: 0.00136

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00302

GnomAD4 exome AF: 0.00110 AC: 600 AN: 545898 Hom.: 7 Cov.: 0 AF XY: 0.000819 AC XY: 242 AN XY: 295520

African (AFR) AF: 0.0246 AC: 384 AN: 15596

American (AMR) AF: 0.00251 AC: 86 AN: 34214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19980

East Asian (EAS) AF: 0.00 AC: 0 AN: 32094

South Asian (SAS) AF: 0.0000322 AC: 2 AN: 62018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33176

Middle Eastern (MID) AF: 0.00164 AC: 4 AN: 2436

European-Non Finnish (NFE) AF: 0.000168 AC: 53 AN: 316042

Other (OTH) AF: 0.00234 AC: 71 AN: 30342

GnomAD4 genome AF: 0.00726 AC: 1102 AN: 151796 Hom.: 21 Cov.: 32 AF XY: 0.00700 AC XY: 519 AN XY: 74160

African (AFR) AF: 0.0241 AC: 997 AN: 41382

American (AMR) AF: 0.00341 AC: 52 AN: 15246

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67916

Other (OTH) AF: 0.00381 AC: 8 AN: 2100

Alfa AF: 0.000508 Hom.: 306

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Xeroderma pigmentosum, group C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.6
DANN	Benign	0.63
PhyloP100		1.6
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: rs2470352; hg19: chr3-14186830;