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

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 scoreres supports a deletorius 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 id is 984262.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.397C>T	p.Gln133*	stop_gained, splice_region_variant	Exon 4 of 12	ENST00000676185.1	NP_000073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.397C>T	p.Gln133*	stop_gained, splice_region_variant	Exon 4 of 12		NM_000082.4	ENSP00000501614.1

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

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32988

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44540

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25942

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39560

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85852

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52916

Gnomad4 NFE exome AF: 9.14e-7 AC: 1 AN: 1094264

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 59702

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cockayne syndrome type 1 Pathogenic:1

Mar 11, 2020

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs1749495521; hg19: chr5-60214094;