chr3-14164948-G-A

Variant names:

• chr3-14164948-G-A
• rs3731116
• NM_004628.5:c.780-15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004628.5(XPC):​c.780-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000597 in 1,603,448 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (5 hom.)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.384
• Publications: 0 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]

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=-0.63).
• BP6: Variant 3-14164948-G-A is Benign according to our data. Variant chr3-14164948-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00313 (477/152290) while in subpopulation AFR AF = 0.011 (456/41562). AF 95% confidence interval is 0.0101. There are 0 homozygotes in GnomAd4. There are 229 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.780-15C>T		intron	N/A	NP_004619.3
	XPC	NM_001354727.2		c.780-15C>T		intron	N/A	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.762-15C>T		intron	N/A	NP_001341658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.780-15C>T		intron	N/A	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*233-15C>T		intron	N/A	ENSP00000424548.1	Q01831-3
	XPC	ENST00000850575.1		c.780-15C>T		intron	N/A	ENSP00000520865.1	A0ABB0MVJ4

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 477 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000816 AC: 195 AN: 239082 AF XY: 0.000739

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000527

GnomAD4 exome AF: 0.000331 AC: 480 AN: 1451158 Hom.: 5 Cov.: 31 AF XY: 0.000305 AC XY: 220 AN XY: 721294

African (AFR) AF: 0.0118 AC: 389 AN: 32828

American (AMR) AF: 0.000585 AC: 25 AN: 42756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39146

South Asian (SAS) AF: 0.0000831 AC: 7 AN: 84236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107348

Other (OTH) AF: 0.000900 AC: 54 AN: 59970

GnomAD4 genome AF: 0.00313 AC: 477 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74468

African (AFR) AF: 0.0110 AC: 456 AN: 41562

American (AMR) AF: 0.00111 AC: 17 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00360

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Xeroderma pigmentosum, group C (3)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Xeroderma pigmentosum group A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.7
DANN	Benign	0.77
PhyloP100		0.38
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: rs3731116; hg19: chr3-14206448;