rs4647128

Variant names:

• chr5-60887717-T-C
• rs4647128
• NM_000082.4:c.1042-197A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000082.4(ERCC8):​c.1042-197A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 152,320 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.024 (62 hom., cov: 33)
• Consequence: ERCC8 NM_000082.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.149
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3658/152320) while in subpopulation NFE AF = 0.0374 (2541/68006). AF 95% confidence interval is 0.0362. There are 62 homozygotes in GnomAd4. There are 1720 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AR gene

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.1042-197A>G		intron	N/A	NP_000073.1	Q13216-1
	ERCC8	NM_001007233.3		c.868-197A>G		intron	N/A	NP_001007234.1	B3KPW7
	ERCC8	NM_001290285.2		c.583-197A>G		intron	N/A	NP_001277214.1	B4DGZ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC8	ENST00000676185.1	MANE Select	c.1042-197A>G		intron	N/A	ENSP00000501614.1	Q13216-1
	ERCC8	ENST00000265038.10	TSL:1	c.1099-197A>G		intron	N/A	ENSP00000265038.6	A0A7I2PE23
	ERCC8	ENST00000891473.1		c.1054-197A>G		intron	N/A	ENSP00000561532.1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3665 AN: 152202 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.00588

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0315

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0240 AC: 3658 AN: 152320 Hom.: 62 Cov.: 33 AF XY: 0.0231 AC XY: 1720 AN XY: 74476

African (AFR) AF: 0.00584 AC: 243 AN: 41588

American (AMR) AF: 0.0230 AC: 352 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4826

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2541 AN: 68006

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0348 Hom.: 136

Bravo AF: 0.0233

Asia WGS AF: 0.0100 AC: 35 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs4647128; hg19: chr5-60183544;