3-14145845-G-C

Variant names:

• chr3-14145845-G-C
• rs2229090
• NM_004628.5:c.*96C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004628.5(XPC):​c.*96C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,460,900 control chromosomes in the GnomAD database, including 47,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4412 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43427 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.21
• Publications: 35 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=-0.84).
• BP6: Variant 3-14145845-G-C is Benign according to our data. Variant chr3-14145845-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 343560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

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.*96C>G		3_prime_UTR	Exon 16 of 16	NP_004619.3
	XPC	NM_001354727.2		c.*96C>G		3_prime_UTR	Exon 16 of 16	NP_001341656.1
	XPC	NM_001354729.2		c.*96C>G		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.*96C>G		3_prime_UTR	Exon 16 of 16	ENSP00000285021.8
	XPC	ENST00000476581.6	TSL:1	n.*2372C>G		non_coding_transcript_exon	Exon 15 of 15	ENSP00000424548.1
	XPC	ENST00000476581.6	TSL:1	n.*2372C>G		3_prime_UTR	Exon 15 of 15	ENSP00000424548.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34451 AN: 151938 Hom.: 4415 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.249 AC: 48463 AN: 194356 AF XY: 0.249

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.388

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.253 AC: 331265 AN: 1308844 Hom.: 43427 Cov.: 19 AF XY: 0.252 AC XY: 163836 AN XY: 650832

African (AFR) AF: 0.108 AC: 3224 AN: 29760

American (AMR) AF: 0.227 AC: 8609 AN: 37856

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 4965 AN: 22818

East Asian (EAS) AF: 0.377 AC: 14395 AN: 38222

South Asian (SAS) AF: 0.207 AC: 16047 AN: 77480

European-Finnish (FIN) AF: 0.344 AC: 16394 AN: 47616

Middle Eastern (MID) AF: 0.195 AC: 744 AN: 3810

European-Non Finnish (NFE) AF: 0.254 AC: 253385 AN: 996716

Other (OTH) AF: 0.247 AC: 13502 AN: 54566

GnomAD4 genome AF: 0.227 AC: 34462 AN: 152056 Hom.: 4412 Cov.: 32 AF XY: 0.231 AC XY: 17188 AN XY: 74324

African (AFR) AF: 0.117 AC: 4866 AN: 41506

American (AMR) AF: 0.247 AC: 3780 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 773 AN: 3470

East Asian (EAS) AF: 0.397 AC: 2039 AN: 5130

South Asian (SAS) AF: 0.213 AC: 1026 AN: 4816

European-Finnish (FIN) AF: 0.364 AC: 3848 AN: 10584

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17130 AN: 67936

Other (OTH) AF: 0.257 AC: 542 AN: 2112

Alfa AF: 0.141 Hom.: 403

Bravo AF: 0.215

Asia WGS AF: 0.261 AC: 905 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Xeroderma pigmentosum, group C (3)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Xeroderma pigmentosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.44
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2229090; hg19: chr3-14187345; COSMIC: COSV53205418; COSMIC: COSV53205418;