3-14148768-G-C

Variant names:

• chr3-14148768-G-C
• rs2470353
• NM_004628.5:c.2251-37C>G

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.2251-37C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,612,902 control chromosomes in the GnomAD database, including 170,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13681 hom., cov: 33)
  • Exomes 𝑓: 0.46 (157183 hom.)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.162
• Publications: 12 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=-0.77).
• BP6: Variant 3-14148768-G-C is Benign according to our data. Variant chr3-14148768-G-C is described in ClinVar as Benign. ClinVar VariationId is 259469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.2251-37C>G		intron_variant	Intron 12 of 15	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.2251-37C>G		intron_variant	Intron 12 of 15	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62953 AN: 151978 Hom.: 13673 Cov.: 33

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.443

GnomAD2 exomes AF: 0.412 AC: 102297 AN: 248198 AF XY: 0.413

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.0405

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.456 AC: 665974 AN: 1460804 Hom.: 157183 Cov.: 74 AF XY: 0.453 AC XY: 329446 AN XY: 726518

African (AFR) AF: 0.355 AC: 11870 AN: 33460

American (AMR) AF: 0.425 AC: 18984 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 11229 AN: 26126

East Asian (EAS) AF: 0.0394 AC: 1563 AN: 39680

South Asian (SAS) AF: 0.391 AC: 33707 AN: 86228

European-Finnish (FIN) AF: 0.461 AC: 24605 AN: 53366

Middle Eastern (MID) AF: 0.352 AC: 2027 AN: 5762

European-Non Finnish (NFE) AF: 0.483 AC: 536177 AN: 1111188

Other (OTH) AF: 0.428 AC: 25812 AN: 60344

GnomAD4 genome AF: 0.414 AC: 63000 AN: 152098 Hom.: 13681 Cov.: 33 AF XY: 0.412 AC XY: 30600 AN XY: 74360

African (AFR) AF: 0.352 AC: 14601 AN: 41472

American (AMR) AF: 0.411 AC: 6286 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1516 AN: 3470

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5174

South Asian (SAS) AF: 0.387 AC: 1866 AN: 4822

European-Finnish (FIN) AF: 0.461 AC: 4885 AN: 10588

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.472 AC: 32116 AN: 67980

Other (OTH) AF: 0.439 AC: 927 AN: 2110

Alfa AF: 0.353 Hom.: 1572

Bravo AF: 0.409

Asia WGS AF: 0.249 AC: 865 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum group A Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Xeroderma pigmentosum, group C Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.7
DANN	Benign	0.81
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
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: rs2470353; hg19: chr3-14190268; COSMIC: COSV53204863; COSMIC: COSV53204863;