3-14145330-A-G

Variant names:

• chr3-14145330-A-G
• rs2470352
• ENST00000608606.1:n.244A>G

Variant summary

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

The ENST00000608606.1(ENSG00000268279):​n.244A>G variant causes a non coding transcript exon 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: ENSG00000268279 ENST00000608606.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.63
• Publications: 15 publications found

Genes affected

ENSG00000268279 (HGNC:):

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

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 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.*611T>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
ENSG00000268279	ENST00000608606.1	n.244A>G		non_coding_transcript_exon_variant	Exon 4 of 5	5		ENSP00000476275.1
XPC	ENST00000285021.12	c.*611T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8

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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group C Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
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;