3-14158973-G-A

Position:

• chr3-14158973-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004628.5(XPC):​c.991-81C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0493 in 1,570,038 control chromosomes in the GnomAD database, including 2,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (173 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2059 hom.)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.15

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]

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-14158973-G-A is Benign according to our data. Variant chr3-14158973-G-A is described in ClinVar as [Benign]. Clinvar id is 1245293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPC	NM_004628.5	c.991-81C>T		intron_variant		ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.991-81C>T		intron_variant		1	NM_004628.5	ENSP00000285021	P1
XPC-AS1	ENST00000627116.2	n.457-6903G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6010 AN: 151950 Hom.: 173 Cov.: 32

Gnomad AFR AF: 0.00955

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00977

Gnomad FIN AF: 0.0607

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0364

GnomAD4 exome AF: 0.0504 AC: 71449 AN: 1417970 Hom.: 2059 AF XY: 0.0495 AC XY: 34914 AN XY: 706034

Gnomad4 AFR exome AF: 0.00732

Gnomad4 AMR exome AF: 0.0186

Gnomad4 ASJ exome AF: 0.0488

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0618

Gnomad4 NFE exome AF: 0.0576

Gnomad4 OTH exome AF: 0.0458

GnomAD4 genome AF: 0.0395 AC: 6008 AN: 152068 Hom.: 173 Cov.: 32 AF XY: 0.0383 AC XY: 2848 AN XY: 74338

Gnomad4 AFR AF: 0.00952

Gnomad4 AMR AF: 0.0282

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00957

Gnomad4 FIN AF: 0.0607

Gnomad4 NFE AF: 0.0626

Gnomad4 OTH AF: 0.0361

Alfa AF: 0.0508 Hom.: 235

Bravo AF: 0.0345

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.6
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs3731127; hg19: chr3-14200473;