dbSNP rs3729587: XPC:c.621+44C>G (chr3-14167125-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004628.5(XPC):c.621+44C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,501,174 control chromosomes in the GnomAD database, including 65,015 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9512 hom., cov: 32)

Exomes 𝑓: 0.28 ( 55503 hom. )

Consequence

XPC
NM_004628.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.387

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

xeroderma pigmentosum group C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, ClinGen, G2P
xeroderma pigmentosum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

XPC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 3-14167125-G-C is Benign according to our data. Variant chr3-14167125-G-C is described in ClinVar as Benign. ClinVar VariationId is 259472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XPC	NM_004628.5	MANE Select	c.621+44C>G	intron	N/A	NP_004619.3
XPC	NM_001354727.2		c.621+44C>G	intron	N/A	NP_001341656.1	A0ABB0MVJ4
XPC	NM_001354729.2		c.603+44C>G	intron	N/A	NP_001341658.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XPC	ENST00000285021.12	TSL:1 MANE Select	c.621+44C>G	intron	N/A	ENSP00000285021.8	Q01831-1
XPC	ENST00000476581.6	TSL:1	n.*74+44C>G	intron	N/A	ENSP00000424548.1	Q01831-3
XPC	ENST00000850575.1		c.621+44C>G	intron	N/A	ENSP00000520865.1	A0ABB0MVJ4

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

51370

AN:

151922

Hom.:

9495

Cov.:

show subpopulations

Gnomad AFR

AF:

0.499

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.232

Gnomad EAS

AF:

0.257

Gnomad SAS

AF:

0.329

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.320

GnomAD2 exomes

AF:

0.306

AC:

54818

AN:

179048

AF XY:

0.296

show subpopulations

Gnomad AFR exome

AF:

0.500

Gnomad AMR exome

AF:

0.452

Gnomad ASJ exome

AF:

0.240

Gnomad EAS exome

AF:

0.266

Gnomad FIN exome

AF:

0.239

Gnomad NFE exome

AF:

0.264

Gnomad OTH exome

AF:

0.279

GnomAD4 exome

AF:

0.282

AC:

380053

AN:

1349134

Hom.:

55503

Cov.:

AF XY:

0.280

AC XY:

186011

AN XY:

663176

show subpopulations

African (AFR)

AF:

0.515

AC:

15273

AN:

29638

American (AMR)

AF:

0.438

AC:

14590

AN:

33300

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

5075

AN:

21892

East Asian (EAS)

AF:

0.252

AC:

9127

AN:

36190

South Asian (SAS)

AF:

0.313

AC:

22251

AN:

71004

European-Finnish (FIN)

AF:

0.239

AC:

12125

AN:

50722

Middle Eastern (MID)

AF:

0.223

AC:

1195

AN:

5358

European-Non Finnish (NFE)

AF:

0.272

AC:

284590

AN:

1045360

Other (OTH)

AF:

0.284

AC:

15827

AN:

55670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

13194

26388

39582

52776

65970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10070

20140

30210

40280

50350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.338

AC:

51445

AN:

152040

Hom.:

9512

Cov.:

AF XY:

0.339

AC XY:

25158

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.499

AC:

20702

AN:

41458

American (AMR)

AF:

0.372

AC:

5676

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

807

AN:

3472

East Asian (EAS)

AF:

0.258

AC:

1332

AN:

5164

South Asian (SAS)

AF:

0.329

AC:

1584

AN:

4820

European-Finnish (FIN)

AF:

0.229

AC:

2415

AN:

10568

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.265

AC:

18007

AN:

67962

Other (OTH)

AF:

0.319

AC:

674

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1692

3383

5075

6766

8458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

494

988

1482

1976

2470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.291

Hom.:

1327

Bravo

AF:

0.358

Asia WGS

AF:

0.342

AC:

1186

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Xeroderma pigmentosum, group C (2)

not specified (1)

Xeroderma pigmentosum group A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.39

(source)

DANN

Benign

0.40

PhyloP100

-0.39

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over