rs4253004

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000124.4(ERCC6):​c.-87C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 152,628 control chromosomes in the GnomAD database, including 676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (676 hom., cov: 34)
  • Exomes 𝑓: 0.057 (0 hom.)
• Consequence: ERCC6 NM_000124.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-49539034-G-T is Benign according to our data. Variant chr10-49539034-G-T is described in ClinVar as Benign. ClinVar VariationId is 300101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

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.-87C>A		5_prime_UTR	Exon 1 of 21	NP_000115.1	Q03468-1
	ERCC6	NM_001277058.2	MANE Plus Clinical	c.-87C>A		5_prime_UTR	Exon 1 of 6	NP_001263987.1	P0DP91-1
	ERCC6	NM_001346440.2		c.-83C>A		5_prime_UTR	Exon 1 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.-87C>A		5_prime_UTR	Exon 1 of 21	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000447839.7	TSL:2 MANE Plus Clinical	c.-87C>A		5_prime_UTR	Exon 1 of 6	ENSP00000387966.2	P0DP91-1
	ERCC6	ENST00000898255.1		c.-83C>A		5_prime_UTR	Exon 1 of 21	ENSP00000568314.1

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8357 AN: 152214 Hom.: 677 Cov.: 34

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.0805

Gnomad FIN AF: 0.0868

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0554

GnomAD4 exome AF: 0.0574 AC: 17 AN: 296 Hom.: 0 Cov.: 0 AF XY: 0.0522 AC XY: 12 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: 0.400 AC: 4 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: 0.0430 AC: 11 AN: 256

Other (OTH) AF: 0.200 AC: 2 AN: 10

GnomAD4 genome AF: 0.0549 AC: 8361 AN: 152332 Hom.: 676 Cov.: 34 AF XY: 0.0607 AC XY: 4525 AN XY: 74488

African (AFR) AF: 0.0105 AC: 438 AN: 41582

American (AMR) AF: 0.133 AC: 2036 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.364 AC: 1877 AN: 5162

South Asian (SAS) AF: 0.0808 AC: 390 AN: 4828

European-Finnish (FIN) AF: 0.0868 AC: 922 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0367 AC: 2497 AN: 68032

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0184 Hom.: 8

Bravo AF: 0.0600

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cockayne syndrome (1)
-	-	1	COFS syndrome (1)
-	-	1	Macular degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.3
DANN	Benign	0.66
PhyloP100		-0.20
PromoterAI		0.13	Neutral
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: rs4253004; hg19: chr10-50747080;