rs4838518

Variant names:

• chr10-49461840-T-C
• rs4838518
• NM_000124.4:c.3779-284A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-49461840-T-C
• chr10-49461840-T-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000124.4(ERCC6):​c.3779-284A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 151,958 control chromosomes in the GnomAD database, including 14,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.43 (14801 hom., cov: 32)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.121
• Publications: 3 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: Myriad Women's Health, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-49461840-T-C is Benign according to our data. Variant chr10-49461840-T-C is described in ClinVar as Benign. ClinVar VariationId is 1233354.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.505 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.3779-284A>G		intron	N/A	NP_000115.1	Q03468-1
	ERCC6	NM_001346440.2		c.3779-284A>G		intron	N/A	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.3779-284A>G		intron	N/A	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000623073.3	TSL:1	n.8163-284A>G		intron	N/A
	ERCC6	ENST00000624341.3	TSL:1	n.*1378-284A>G		intron	N/A	ENSP00000485163.1	A0A096LNQ7

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64657 AN: 151840 Hom.: 14804 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.426 AC: 64667 AN: 151958 Hom.: 14801 Cov.: 32 AF XY: 0.425 AC XY: 31538 AN XY: 74280

African (AFR) AF: 0.252 AC: 10455 AN: 41452

American (AMR) AF: 0.468 AC: 7148 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3466

East Asian (EAS) AF: 0.483 AC: 2493 AN: 5160

South Asian (SAS) AF: 0.466 AC: 2242 AN: 4816

European-Finnish (FIN) AF: 0.440 AC: 4637 AN: 10550

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34620 AN: 67926

Other (OTH) AF: 0.434 AC: 918 AN: 2114

Alfa AF: 0.452 Hom.: 2043

Bravo AF: 0.422

Asia WGS AF: 0.472 AC: 1637 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.80
PhyloP100		-0.12
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4838518;

hg19: chr10-50669886;