chr3-14145257-C-G

Variant names:

• chr3-14145257-C-G
• rs1126547
• NM_004628.5:c.*684G>C

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.*684G>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 0.886 in 686,448 control chromosomes in the GnomAD database, including 270,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59278 hom., cov: 33)
  • Exomes 𝑓: 0.89 (210734 hom.)
• Consequence: XPC NM_004628.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0480
• Publications: 14 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 3-14145257-C-G is Benign according to our data. Variant chr3-14145257-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 343550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.*684G>C		3_prime_UTR	Exon 16 of 16	NP_004619.3
	XPC	NM_001354727.2		c.*684G>C		3_prime_UTR	Exon 16 of 16	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.*684G>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.*684G>C		3_prime_UTR	Exon 16 of 16	ENSP00000285021.8	Q01831-1
	ENSG00000268279	ENST00000608606.1	TSL:5	n.236-65C>G		intron	N/A	ENSP00000476275.1	V9GY05
	XPC	ENST00000850575.1		c.*684G>C		3_prime_UTR	Exon 16 of 16	ENSP00000520865.1	A0ABB0MVJ4

Frequencies

GnomAD3 genomes AF: 0.882 AC: 134115 AN: 152134 Hom.: 59223 Cov.: 33

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.883

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.928

Gnomad FIN AF: 0.909

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.888

GnomAD2 exomes AF: 0.904 AC: 109766 AN: 121382 AF XY: 0.902

Gnomad AFR exome AF: 0.876

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.877

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.910

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.890

GnomAD4 exome AF: 0.887 AC: 473977 AN: 534196 Hom.: 210734 Cov.: 0 AF XY: 0.888 AC XY: 256281 AN XY: 288562

African (AFR) AF: 0.871 AC: 13378 AN: 15368

American (AMR) AF: 0.936 AC: 31575 AN: 33744

Ashkenazi Jewish (ASJ) AF: 0.879 AC: 16818 AN: 19128

East Asian (EAS) AF: 0.991 AC: 31700 AN: 32000

South Asian (SAS) AF: 0.923 AC: 55583 AN: 60238

European-Finnish (FIN) AF: 0.907 AC: 29591 AN: 32626

Middle Eastern (MID) AF: 0.869 AC: 2062 AN: 2374

European-Non Finnish (NFE) AF: 0.864 AC: 266782 AN: 308826

Other (OTH) AF: 0.886 AC: 26488 AN: 29892

GnomAD4 genome AF: 0.882 AC: 134230 AN: 152252 Hom.: 59278 Cov.: 33 AF XY: 0.886 AC XY: 65973 AN XY: 74436

African (AFR) AF: 0.872 AC: 36209 AN: 41540

American (AMR) AF: 0.924 AC: 14124 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.883 AC: 3067 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5173 AN: 5186

South Asian (SAS) AF: 0.929 AC: 4489 AN: 4834

European-Finnish (FIN) AF: 0.909 AC: 9625 AN: 10586

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.861 AC: 58571 AN: 68028

Other (OTH) AF: 0.889 AC: 1877 AN: 2112

Alfa AF: 0.859 Hom.: 6169

Bravo AF: 0.885

Asia WGS AF: 0.958 AC: 3331 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/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	6.0
DANN	Benign	0.56
PhyloP100		0.048
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: rs1126547; hg19: chr3-14186757;