NM_000124.4:c.*3684A>G

Variant names:

• chr10-49455131-T-C
• rs570822434
• NM_000124.4:c.*3684A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000124.4(ERCC6):​c.*3684A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 152,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0014 (1 hom., cov: 33)
• Consequence: ERCC6 NM_000124.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: -1.72
• Publications: 0 publications found

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

ERCC6 Gene-Disease associations (from GenCC):

• Cockayne spectrum with or without cerebrooculofacioskeletal syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Cockayne syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• UV-sensitive syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• UV-sensitive syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• premature ovarian failure 11

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000235939 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000124.4. 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
	ERCC6	NM_000124.4	MANE Select	c.*3684A>G		3_prime_UTR	Exon 21 of 21	NP_000115.1	Q03468-1
	ERCC6	NM_001346440.2		c.*3684A>G		3_prime_UTR	Exon 21 of 21	NP_001333369.1	Q03468-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.*3684A>G		3_prime_UTR	Exon 21 of 21	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000681659.1		c.*3684A>G		3_prime_UTR	Exon 20 of 20	ENSP00000505631.1	A0A7P0T9G4
	ERCC6	ENST00000679871.1		n.5312A>G		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152172 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000958

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

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152172 Hom.: 1 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74334

African (AFR) AF: 0.000458 AC: 19 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00651 AC: 69 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68034

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000960

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Age related macular degeneration 5 (1)
-	1	-	Cerebrooculofacioskeletal syndrome 1 (1)
-	1	-	Cockayne syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.59
DANN	Benign	0.58
PhyloP100		-1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs570822434; hg19: chr10-50663177;