5-60940379-A-G

Variant names:

• chr5-60940379-A-G
• rs158937
• NM_000082.4:c.77+4553T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000082.4(ERCC8):​c.77+4553T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.874 in 152,190 control chromosomes in the GnomAD database, including 58,350 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 0.87 (58350 hom., cov: 32)
• Consequence: ERCC8 NM_000082.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.799
• Publications: 5 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: Laboratory for Molecular Medicine, Genomics England PanelApp, PanelApp Australia, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC8	NM_000082.4	MANE Select	c.77+4553T>C		intron	N/A	NP_000073.1
	ERCC8	NM_001007233.3		c.-316+4553T>C		intron	N/A	NP_001007234.1
	ERCC8	NM_001290285.2		c.-301+4553T>C		intron	N/A	NP_001277214.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC8	ENST00000676185.1	MANE Select	c.77+4553T>C		intron	N/A	ENSP00000501614.1
	ERCC8	ENST00000265038.10	TSL:1	c.77+4553T>C		intron	N/A	ENSP00000265038.6
	ERCC8	ENST00000497892.6	TSL:1	n.77+4553T>C		intron	N/A	ENSP00000501805.1

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132854 AN: 152072 Hom.: 58320 Cov.: 32

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.945

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.839

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.869

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

GnomAD4 genome AF: 0.874 AC: 132938 AN: 152190 Hom.: 58350 Cov.: 32 AF XY: 0.874 AC XY: 65050 AN XY: 74396

African (AFR) AF: 0.787 AC: 32646 AN: 41492

American (AMR) AF: 0.891 AC: 13622 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.839 AC: 2910 AN: 3470

East Asian (EAS) AF: 0.946 AC: 4897 AN: 5174

South Asian (SAS) AF: 0.887 AC: 4284 AN: 4828

European-Finnish (FIN) AF: 0.929 AC: 9843 AN: 10600

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61786 AN: 68022

Other (OTH) AF: 0.870 AC: 1841 AN: 2116

Alfa AF: 0.881 Hom.: 7672

Bravo AF: 0.868

Asia WGS AF: 0.913 AC: 3176 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.35
PhyloP100		-0.80
Mutation Taster		=100/0	polymorphism (auto)

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: rs158937; hg19: chr5-60236206;