NM_004628.5:c.*684G>C

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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.*684G>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.*684G>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8
ENSG00000268279	ENST00000608606.1	n.236-65C>G		intron_variant	Intron 3 of 4	5		ENSP00000476275.1

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum, group C Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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;