rs4253004

Variant names:

• chr10-49539034-G-A
• rs4253004
• NM_000124.4:c.-87C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-49539034-G-A
• chr10-49539034-G-C
• chr10-49539034-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000124.4(ERCC6):​c.-87C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ERCC6 NM_000124.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.199
• Publications: 9 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: G2P, Myriad Women’s Health, Orphanet, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.-87C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001277058.2	c.-87C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	ENST00000447839.7	NP_001263987.1
ERCC6	NM_000124.4	c.-87C>T		5_prime_UTR_variant	Exon 1 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001277058.2	c.-87C>T		5_prime_UTR_variant	Exon 1 of 6	ENST00000447839.7	NP_001263987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.-87C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 21	1	NM_000124.4	ENSP00000348089.5
ERCC6	ENST00000447839.7	c.-87C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	2	NM_001277058.2	ENSP00000387966.2
ERCC6	ENST00000355832.10	c.-87C>T		5_prime_UTR_variant	Exon 1 of 21	1	NM_000124.4	ENSP00000348089.5
ERCC6	ENST00000447839.7	c.-87C>T		5_prime_UTR_variant	Exon 1 of 6	2	NM_001277058.2	ENSP00000387966.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 296 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 230

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 256

Other (OTH) AF: 0.00 AC: 0 AN: 10

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.4
DANN	Benign	0.80
PhyloP100		-0.20
PromoterAI		0.17	Neutral

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: rs4253004; hg19: chr10-50747080;