rs4235483

Positions:

• chr5-60892395-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000082.4(ERCC8):​c.844-1309G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 542,060 control chromosomes in the GnomAD database, including 36,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.37 (10697 hom., cov: 31)
  • Exomes 𝑓: 0.35 (25436 hom.)
• Consequence: ERCC8 NM_000082.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96

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]

GNL3LP1 (HGNC:25733): (G protein nucleolar 3 like pseudogene 1)

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-60892395-C-T is Benign according to our data. Variant chr5-60892395-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC8	NM_000082.4	c.844-1309G>A		intron_variant		ENST00000676185.1
ERCC8	NM_001007233.3	c.670-1309G>A		intron_variant
ERCC8	NM_001290285.2	c.385-1309G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC8	ENST00000676185.1	c.844-1309G>A		intron_variant			NM_000082.4	P1
GNL3LP1	ENST00000399458.2	n.1183G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55784 AN: 151824 Hom.: 10681 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.350 AC: 136398 AN: 390118 Hom.: 25436 Cov.: 0 AF XY: 0.352 AC XY: 77383 AN XY: 220008

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.236

Gnomad4 ASJ exome AF: 0.408

Gnomad4 EAS exome AF: 0.0538

Gnomad4 SAS exome AF: 0.327

Gnomad4 FIN exome AF: 0.377

Gnomad4 NFE exome AF: 0.388

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.367 AC: 55831 AN: 151942 Hom.: 10697 Cov.: 31 AF XY: 0.364 AC XY: 27040 AN XY: 74238

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.429

Gnomad4 EAS AF: 0.0570

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.394

Gnomad4 OTH AF: 0.379

Alfa AF: 0.383 Hom.: 2298

Bravo AF: 0.363

Asia WGS AF: 0.183 AC: 636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.9
DANN	Benign	0.51

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: rs4235483; hg19: chr5-60188222; COSMIC: COSV54015135;