3-14167193-T-C

Variant names:

• chr3-14167193-T-C
• rs587778759
• NM_004628.5:c.597A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_004628.5(XPC):​c.597A>G​(p.Lys199Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPC NM_004628.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.599
• Publications: 0 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 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-14167193-T-C is Benign according to our data. Variant chr3-14167193-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2034376.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.599 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	NM_004628.5	MANE Select	c.597A>G	p.Lys199Lys	synonymous	Exon 5 of 16	NP_004619.3
	XPC	NM_001354727.2		c.597A>G	p.Lys199Lys	synonymous	Exon 5 of 16	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.579A>G	p.Lys193Lys	synonymous	Exon 5 of 16	NP_001341658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.597A>G	p.Lys199Lys	synonymous	Exon 5 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*50A>G		non_coding_transcript_exon	Exon 4 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000476581.6	TSL:1	n.*50A>G		3_prime_UTR	Exon 4 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.8
DANN	Benign	0.26
PhyloP100		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs587778759; hg19: chr3-14208693;