13-102875698-C-T

Variant names:

• chr13-102875698-C-T
• rs2227871
• NM_000123.4:c.3356C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000123.4(ERCC5):​c.3356C>T​(p.Ala1119Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,006 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: -0.214
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044332743).
• BP6: Variant 13-102875698-C-T is Benign according to our data. Variant chr13-102875698-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134169.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	NM_000123.4	MANE Select	c.3356C>T	p.Ala1119Val	missense	Exon 15 of 15	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.4718C>T	p.Ala1573Val	missense	Exon 23 of 23	NP_001191354.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	ENST00000652225.2	MANE Select	c.3356C>T	p.Ala1119Val	missense	Exon 15 of 15	ENSP00000498881.2
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.4718C>T	p.Ala1573Val	missense	Exon 25 of 25	ENSP00000491742.1
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.4031C>T	p.Ala1344Val	missense	Exon 24 of 24	ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00331

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00118 AC: 297 AN: 251214 AF XY: 0.00127

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00122 AC: 1780 AN: 1461876 Hom.: 8 Cov.: 35 AF XY: 0.00121 AC XY: 883 AN XY: 727240

African (AFR) AF: 0.000568 AC: 19 AN: 33478

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00210 AC: 181 AN: 86252

European-Finnish (FIN) AF: 0.00185 AC: 99 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00120 AC: 1339 AN: 1112008

Other (OTH) AF: 0.00139 AC: 84 AN: 60394

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74358

African (AFR) AF: 0.000651 AC: 27 AN: 41498

American (AMR) AF: 0.00131 AC: 20 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4822

European-Finnish (FIN) AF: 0.00331 AC: 35 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00124 AC: 84 AN: 67996

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00132 AC: 160

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	ERCC5-related disorder (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Xeroderma pigmentosum, group G (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.25
DANN	Benign	0.82
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.28	N
PhyloP100		-0.21
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.0070
Sift	Benign	0.11	T
Sift4G	Benign	0.33	T
Polyphen		0.0040	B
Vest4		0.076
MVP		0.17
MPC		0.11
ClinPred		0.0035	T
GERP RS		-3.0
Varity_R		0.029
gMVP		0.15
Mutation Taster		=98/2	polymorphism

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: rs2227871; hg19: chr13-103528048; COSMIC: COSV105916300; COSMIC: COSV105916300;