rs201126529

chr5-60903733-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000082.4(ERCC8):c.482-17C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,610,122 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: ERCC8 NM_000082.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-60903733-G-A is Benign according to our data. Variant chr5-60903733-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 254943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000395 (60/151918) while in subpopulation EAS AF= 0.00387 (20/5172). AF 95% confidence interval is 0.00256. There are 1 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC8	NM_000082.4	c.482-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000676185.1
ERCC8	NM_001007233.3	c.308-17C>T		splice_polypyrimidine_tract_variant, intron_variant
ERCC8	NM_001007234.3	c.482-17C>T		splice_polypyrimidine_tract_variant, intron_variant
ERCC8	NM_001290285.2	c.23-17C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1	c.482-17C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_000082.4	P1

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 151800 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000551 AC: 138 AN: 250412 Hom.: 0 AF XY: 0.000539 AC XY: 73 AN XY: 135410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00223

Gnomad SAS exome AF: 0.000329

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000368 AC: 537 AN: 1458204 Hom.: 1 Cov.: 30 AF XY: 0.000360 AC XY: 261 AN XY: 725532

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00468

Gnomad4 EAS exome AF: 0.00521

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.0000865

Gnomad4 OTH exome AF: 0.000482

GnomAD4 genome AF: 0.000395 AC: 60 AN: 151918 Hom.: 1 Cov.: 30 AF XY: 0.000539 AC XY: 40 AN XY: 74220

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000502 Hom.: 0

Bravo AF: 0.000268

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.54
Dann	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs201126529; hg19: chr5-60199560;