rs121434325

Variant names:

• chr5-60904794-G-A
• rs121434325
• NM_000082.4:c.479C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-60904794-G-A
• chr5-60904794-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000082.4(ERCC8):​c.479C>T​(p.Ala160Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000948 in 1,582,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000521089: Published studies demonstrate a damaging effect" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A160T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: ERCC8 NM_000082.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1 O:1
• Conservation: PhyloP100: 8.33
• Publications: 5 publications found

Genes affected

ERCC8 (HGNC:3439): (ERCC excision repair 8, CSA ubiquitin ligase complex subunit) This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

ERCC8 Gene-Disease associations (from GenCC):

• Cockayne syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Myriad Women’s Health, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• UV-sensitive syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Cockayne syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• UV-sensitive syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000521089: Published studies demonstrate a damaging effect; specifically, this variant causes the deletion of exon 5 in the transcipt (Nardo et al., 2009); SCV001575796: Studies have shown that this missense change results in deletion of exon 5 and introduces a premature termination codon (PMID: 15744458).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-60904795-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 68753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 5-60904794-G-A is Pathogenic according to our data. Variant chr5-60904794-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000082.4. 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
	ERCC8	NM_000082.4	MANE Select	c.479C>T	p.Ala160Val	missense splice_region	Exon 5 of 12	NP_000073.1	Q13216-1
	ERCC8	NM_001007233.3		c.305C>T	p.Ala102Val	missense splice_region	Exon 6 of 13	NP_001007234.1	B3KPW7
	ERCC8	NM_001007234.3		c.479C>T	p.Ala160Val	missense splice_region	Exon 5 of 6	NP_001007235.1	Q13216-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC8	ENST00000676185.1	MANE Select	c.479C>T	p.Ala160Val	missense splice_region	Exon 5 of 12	ENSP00000501614.1	Q13216-1
	ERCC8	ENST00000265038.10	TSL:1	c.479C>T	p.Ala160Val	missense splice_region	Exon 5 of 13	ENSP00000265038.6	A0A7I2PE23
	ERCC8	ENST00000497892.6	TSL:1	n.*277C>T		splice_region non_coding_transcript_exon	Exon 6 of 7	ENSP00000501805.1	A0A6Q8PFI5

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150466 Hom.: 0 Cov.: 26

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250708 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000978 AC: 14 AN: 1431894 Hom.: 0 Cov.: 25 AF XY: 0.00000980 AC XY: 7 AN XY: 714194

African (AFR) AF: 0.00 AC: 0 AN: 33014

American (AMR) AF: 0.00 AC: 0 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 85374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1085474

Other (OTH) AF: 0.00 AC: 0 AN: 59302

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150466 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 73346

African (AFR) AF: 0.00 AC: 0 AN: 41064

American (AMR) AF: 0.00 AC: 0 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67648

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.0000453 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (4)
1	1	-	Cockayne syndrome type 1 (2)
1	-	-	Cockayne syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.39		Loss of ubiquitination at K155 (P = 0.1264)
MVP		0.90
MPC		0.28
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.81
gMVP		0.43
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: -2

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

Other links and lift over

dbSNP: rs121434325; hg19: chr5-60200621;