3-14145671-T-C

Variant names:

• chr3-14145671-T-C
• rs564228132
• ENST00000608606.1:n.*186T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000608606.1(ENSG00000268279):​n.*186T>C 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 0.00107 in 699,412 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: ENSG00000268279 ENST00000608606.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.317
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-14145671-T-C is Benign according to our data. Variant chr3-14145671-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 343557.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.*270A>G		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.*186T>C		non_coding_transcript_exon_variant	Exon 4 of 5	5		ENSP00000476275.1
XPC	ENST00000285021.12	c.*270A>G		3_prime_UTR_variant	Exon 16 of 16	1	NM_004628.5	ENSP00000285021.8
ENSG00000268279	ENST00000608606.1	n.*186T>C		3_prime_UTR_variant	Exon 4 of 5	5		ENSP00000476275.1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00161 AC: 211 AN: 131442 AF XY: 0.00175

Gnomad AFR exome AF: 0.000160

Gnomad AMR exome AF: 0.000615

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00174

GnomAD4 exome AF: 0.00120 AC: 659 AN: 547080 Hom.: 8 Cov.: 0 AF XY: 0.00140 AC XY: 414 AN XY: 296346

African (AFR) AF: 0.00 AC: 0 AN: 15724

American (AMR) AF: 0.000605 AC: 21 AN: 34700

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 222 AN: 20018

East Asian (EAS) AF: 0.00 AC: 0 AN: 32082

South Asian (SAS) AF: 0.00340 AC: 210 AN: 61840

European-Finnish (FIN) AF: 0.000121 AC: 4 AN: 33086

Middle Eastern (MID) AF: 0.00164 AC: 4 AN: 2446

European-Non Finnish (NFE) AF: 0.000470 AC: 149 AN: 316794

Other (OTH) AF: 0.00161 AC: 49 AN: 30390

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152332 Hom.: 1 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74504

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.000392 AC: 6 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68032

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00214 Hom.: 1

Bravo AF: 0.000567

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Xeroderma pigmentosum, group C Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.6
DANN	Benign	0.70
PhyloP100		-0.32
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: rs564228132; hg19: chr3-14187171;