rs2607775

Variant names:

• chr3-14178595-C-G
• rs2607775
• ENST00000476581.6:n.-27G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000476581.6(XPC):​n.-27G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,612,026 control chromosomes in the GnomAD database, including 172,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14100 hom., cov: 34)
  • Exomes 𝑓: 0.46 (158875 hom.)
• Consequence: XPC ENST00000476581.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.90
• Publications: 41 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]

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-14178595-C-G is Benign according to our data. Variant chr3-14178595-C-G is described in ClinVar as Benign. ClinVar VariationId is 259465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.-27G>C		5_prime_UTR_variant	Exon 1 of 16	ENST00000285021.12	NP_004619.3
LSM3	NM_014463.3	c.-266C>G		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.-27G>C		5_prime_UTR_variant	Exon 1 of 16	1	NM_004628.5	ENSP00000285021.8
LSM3	ENST00000306024.4	c.-266C>G		upstream_gene_variant		1	NM_014463.3	ENSP00000302160.3

Frequencies

GnomAD3 genomes AF: 0.421 AC: 64108 AN: 152102 Hom.: 14088 Cov.: 34

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.447

GnomAD2 exomes AF: 0.415 AC: 102197 AN: 246200 AF XY: 0.416

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.0409

Gnomad FIN exome AF: 0.461

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.458 AC: 669200 AN: 1459806 Hom.: 158875 Cov.: 45 AF XY: 0.456 AC XY: 331040 AN XY: 726302

African (AFR) AF: 0.375 AC: 12548 AN: 33458

American (AMR) AF: 0.428 AC: 19081 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11006 AN: 26098

East Asian (EAS) AF: 0.0396 AC: 1572 AN: 39672

South Asian (SAS) AF: 0.391 AC: 33759 AN: 86232

European-Finnish (FIN) AF: 0.461 AC: 24103 AN: 52274

Middle Eastern (MID) AF: 0.353 AC: 2036 AN: 5768

European-Non Finnish (NFE) AF: 0.485 AC: 539084 AN: 1111358

Other (OTH) AF: 0.431 AC: 26011 AN: 60316

GnomAD4 genome AF: 0.421 AC: 64159 AN: 152220 Hom.: 14100 Cov.: 34 AF XY: 0.419 AC XY: 31190 AN XY: 74434

African (AFR) AF: 0.373 AC: 15489 AN: 41550

American (AMR) AF: 0.415 AC: 6351 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1485 AN: 3470

East Asian (EAS) AF: 0.0422 AC: 218 AN: 5170

South Asian (SAS) AF: 0.387 AC: 1871 AN: 4830

European-Finnish (FIN) AF: 0.462 AC: 4901 AN: 10598

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32322 AN: 67976

Other (OTH) AF: 0.443 AC: 938 AN: 2116

Alfa AF: 0.442 Hom.: 2780

Bravo AF: 0.417

Asia WGS AF: 0.253 AC: 881 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

Xeroderma pigmentosum, group C Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.9
DANN	Benign	0.77
PhyloP100		-2.9
PromoterAI		-0.093	Neutral
Mutation Taster		=300/0	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: rs2607775; hg19: chr3-14220095; COSMIC: COSV53204236;