3-14178568-T-C

Variant names:

• chr3-14178568-T-C
• rs763678756
• NM_004628.5:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Supporting PM2 PP5

The NM_004628.5(XPC):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,532 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: XPC NM_004628.5 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.23

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]

LSM3 (HGNC:17874): (LSM3 homolog, U6 small nuclear RNA and mRNA degradation associated) Sm-like proteins were identified in a variety of organisms based on sequence homology with the Sm protein family (see SNRPD2; MIM 601061). Sm-like proteins contain the Sm sequence motif, which consists of 2 regions separated by a linker of variable length that folds as a loop. The Sm-like proteins are thought to form a stable heteromer present in tri-snRNP particles, which are important for pre-mRNA splicing.[supplied by OMIM, Apr 2004]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 118 codons. Genomic position: 14170498. Lost 0.125 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-14178568-T-C is Pathogenic according to our data. Variant chr3-14178568-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551388.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.1A>G	p.Met1?	start_lost	Exon 1 of 16	ENST00000285021.12	NP_004619.3
LSM3	NM_014463.3	c.-293T>C		upstream_gene_variant		ENST00000306024.4	NP_055278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.1A>G	p.Met1?	start_lost	Exon 1 of 16	1	NM_004628.5	ENSP00000285021.8
XPC	ENST00000476581.6	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 15	1		ENSP00000424548.1
XPC	ENST00000511155.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 4	4		ENSP00000423867.1
LSM3	ENST00000306024.4	c.-293T>C		upstream_gene_variant		1	NM_014463.3	ENSP00000302160.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000525 AC: 13 AN: 247852 Hom.: 0 AF XY: 0.0000593 AC XY: 8 AN XY: 134850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000624

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1460288 Hom.: 1 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726516

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Xeroderma pigmentosum, group C Pathogenic:2 Uncertain:1

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Xeroderma pigmentosum Pathogenic:1

Dec 06, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: XPC c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met118) is located in the encoded protein. An activation of potential downstream translation at this initiation site would result in a shortened protein missing the first 117 amino acids from the protein sequence. Two of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 247852 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in XPC causing Xeroderma Pigmentosum (5.2e-05 vs 0.00071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1A>G in individuals affected with Xeroderma Pigmentosum and no experimental evidence demonstrating its impact on protein function have been reported. However, another variant affecting the ATG initiation codon of XPC, c.2T>G (p.Met1Arg), has been reported in individuals affected with Xeroderma Pigmentosa (Khan_2009). This change has also been shown to severely impair protein expression (Khan_2009), suggesting that variants affecting the start codon of XPC are likely to impact function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Dec 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the XPC mRNA. The next in-frame methionine is located at codon 118. This variant is present in population databases (rs763678756, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with xeroderma pigmentosum (PMID: 18955168). ClinVar contains an entry for this variant (Variation ID: 551388). Studies have shown that disruption of the initiator codon alters XPC gene expression (PMID: 18955168). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.89	T
PROVEAN	Benign	-1.5	N;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.010	B;.
Vest4		0.80
MutPred		0.87		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.42
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs763678756; hg19: chr3-14220068;