13-102852241-G-T

Variant names:

• chr13-102852241-G-T
• NM_000123.4:c.212G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000123.4(ERCC5):​c.212G>T​(p.Arg71Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.66

Genes affected

ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

BIVM-ERCC5 (HGNC:43690): (BIVM-ERCC5 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BIVM (basic, immunoglobulin-like variable motif containing) and ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5) genes on chromosome 13. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.212G>T	p.Arg71Leu	missense_variant	Exon 2 of 15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.1574G>T	p.Arg525Leu	missense_variant	Exon 10 of 23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.212G>T	p.Arg71Leu	missense_variant	Exon 2 of 15		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.1574G>T	p.Arg525Leu	missense_variant	Exon 12 of 25	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.887G>T	p.Arg296Leu	missense_variant	Exon 11 of 24	5		ENSP00000492684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	.;.;.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.0	.;.;.;M;M
PROVEAN	Pathogenic	-5.7	.;.;.;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.025	.;.;.;D;D
Sift4G	Uncertain	0.0070	.;.;.;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.78, 0.82
MutPred		0.66		.;.;.;Gain of catalytic residue at P72 (P = 0.001);Gain of catalytic residue at P72 (P = 0.001);
MVP		0.82
MPC		0.59
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-103504591;