5-60918267-G-A

Variant names:

• chr5-60918267-G-A
• rs1749495521
• NM_000082.4:c.397C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_000082.4(ERCC8):​c.397C>T​(p.Gln133*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000000694 in 1,441,480 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ERCC8 NM_000082.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9966
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.92
• Publications: 1 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-AS1 (HGNC:40220): (ERCC8 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• 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 5-60918267-G-A is Pathogenic according to our data. Variant chr5-60918267-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 984262.Status of the report is criteria_provided_single_submitter, 1 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.397C>T	p.Gln133*	stop_gained splice_region	Exon 4 of 12	NP_000073.1	Q13216-1
	ERCC8	NM_001007233.3		c.223C>T	p.Gln75*	stop_gained splice_region	Exon 5 of 13	NP_001007234.1	B3KPW7
	ERCC8	NM_001290285.2		c.20C>T	p.Thr7Ile	missense splice_region	Exon 4 of 11	NP_001277214.1	B4DGZ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC8	ENST00000676185.1	MANE Select	c.397C>T	p.Gln133*	stop_gained splice_region	Exon 4 of 12	ENSP00000501614.1	Q13216-1
	ERCC8	ENST00000265038.10	TSL:1	c.397C>T	p.Gln133*	stop_gained splice_region	Exon 4 of 13	ENSP00000265038.6	A0A7I2PE23
	ERCC8	ENST00000497892.6	TSL:1	n.*195C>T		splice_region non_coding_transcript_exon	Exon 5 of 7	ENSP00000501805.1	A0A6Q8PFI5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441480 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 718400

African (AFR) AF: 0.00 AC: 0 AN: 32988

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094264

Other (OTH) AF: 0.00 AC: 0 AN: 59702

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cockayne syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		3.9
Vest4		0.86
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: -2

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

Other links and lift over

dbSNP: rs1749495521; hg19: chr5-60214094;