chr3-14148737-T-G

Position:

chr3-14148737-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004628.5(XPC):c.2251-6A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,613,516 control chromosomes in the GnomAD database, including 304,401 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 31584 hom., cov: 32)

Exomes 𝑓: 0.61 ( 272817 hom. )

Consequence

XPC
NM_004628.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004812

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0560

Variant links:

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 links:

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

XPC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 3-14148737-T-G is Benign according to our data. Variant chr3-14148737-T-G is described in ClinVar as [Benign]. Clinvar id is 190214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPC	NM_004628.5 linkuse as main transcript	c.2251-6A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000285021.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPC	ENST00000285021.12 linkuse as main transcript	c.2251-6A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004628.5	P1	Q01831-1
XPC-AS1	ENST00000627116.2 linkuse as main transcript	n.300+36T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.642

AC:

97494

AN:

151914

Hom.:

31541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.705

Gnomad AMI

AF:

0.641

Gnomad AMR

AF:

0.668

Gnomad ASJ

AF:

0.533

Gnomad EAS

AF:

0.637

Gnomad SAS

AF:

0.656

Gnomad FIN

AF:

0.700

Gnomad MID

AF:

0.484

Gnomad NFE

AF:

0.594

Gnomad OTH

AF:

0.641

GnomAD3 exomes

AF:

0.633

AC:

157405

AN:

248834

Hom.:

50207

AF XY:

0.626

AC XY:

84558

AN XY:

135002

show subpopulations

Gnomad AFR exome

AF:

0.709

Gnomad AMR exome

AF:

0.705

Gnomad ASJ exome

AF:

0.530

Gnomad EAS exome

AF:

0.640

Gnomad SAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.698

Gnomad NFE exome

AF:

0.593

Gnomad OTH exome

AF:

0.603

GnomAD4 exome

AF:

0.609

AC:

890414

AN:

1461484

Hom.:

272817

Cov.:

AF XY:

0.608

AC XY:

442169

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.707

Gnomad4 AMR exome

AF:

0.702

Gnomad4 ASJ exome

AF:

0.529

Gnomad4 EAS exome

AF:

0.618

Gnomad4 SAS exome

AF:

0.646

Gnomad4 FIN exome

AF:

0.692

Gnomad4 NFE exome

AF:

0.598

Gnomad4 OTH exome

AF:

0.603

GnomAD4 genome

AF:

0.642

AC:

97611

AN:

152032

Hom.:

31584

Cov.:

AF XY:

0.648

AC XY:

48128

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.705

Gnomad4 AMR

AF:

0.668

Gnomad4 ASJ

AF:

0.533

Gnomad4 EAS

AF:

0.637

Gnomad4 SAS

AF:

0.658

Gnomad4 FIN

AF:

0.700

Gnomad4 NFE

AF:

0.594

Gnomad4 OTH

AF:

0.644

Alfa

AF:

0.608

Hom.:

12795

Bravo

AF:

0.642

Asia WGS

AF:

0.677

AC:

2354

AN:

3478

EpiCase

AF:

0.570

EpiControl

AF:

0.573

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 12177305, 19027756, 21559836, 10766188) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	XPC: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2017	Variant summary: The XPC c.2251-6A>C variant involves the alteration of a non-conserved intronic nucleotide and 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 75910/120462 control chromosomes (24122 homozygotes) at a frequency of 0.6301572, which is approximately 446 times the estimated maximal expected allele frequency of a pathogenic XPC variant (0.0014142). The observed frequency indicate that the C allele is the major allele observed in the general population. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jun 20, 2012	- -

Xeroderma pigmentosum, group C

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Xeroderma pigmentosum group A

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.9

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000048

dbscSNV1_RF

Benign

0.046

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over