NM_000124.4:c.1337G>A

Variant names:

• chr10-49524093-C-T
• rs4253047
• NM_000124.4:c.1337G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000124.4(ERCC6):​c.1337G>A​(p.Gly446Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,966 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (9 hom., cov: 32)
  • Exomes 𝑓: 0.014 (154 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.40
• Publications: 18 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]

PGBD3 (HGNC:19400): (piggyBac transposable element derived 3) This gene is a member of a small family of genes derived from piggyBac transposable elements. The encoded protein contains a zinc-ribbon domain characteristic of transposon-derived proteins and may function as a regulator of transcription. Alternative splicing occurs between a splice site from exon 5 of the adjacent upstream gene 'excision repair cross-complementation group 6' (ERCC6, GeneID: 2074) and the 3' splice site upstream of the open reading frame (ORF) of this gene, 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. Pseudogenes for this gene are defined on chromosomes 4, 5 and 12. [provided by RefSeq, Mar 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059863925).
• BP6: Variant 10-49524093-C-T is Benign according to our data. Variant chr10-49524093-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00982 (1494/152068) while in subpopulation NFE AF = 0.0151 (1027/67970). AF 95% confidence interval is 0.0143. There are 9 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,Unknown gene

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.1337G>A	p.Gly446Asp	missense	Exon 5 of 21	NP_000115.1	Q03468-1
	ERCC6	NM_001277058.2	MANE Plus Clinical	c.1337G>A	p.Gly446Asp	missense	Exon 5 of 6	NP_001263987.1	P0DP91-1
	ERCC6	NM_001346440.2		c.1337G>A	p.Gly446Asp	missense	Exon 5 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.1337G>A	p.Gly446Asp	missense	Exon 5 of 21	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000447839.7	TSL:2 MANE Plus Clinical	c.1337G>A	p.Gly446Asp	missense	Exon 5 of 6	ENSP00000387966.2	P0DP91-1
	ERCC6	ENST00000898255.1		c.1337G>A	p.Gly446Asp	missense	Exon 5 of 21	ENSP00000568314.1

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1495 AN: 151950 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00905

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00953 AC: 2367 AN: 248338 AF XY: 0.00962

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.00899

GnomAD4 exome AF: 0.0140 AC: 20401 AN: 1460898 Hom.: 154 Cov.: 31 AF XY: 0.0135 AC XY: 9806 AN XY: 726804

African (AFR) AF: 0.00242 AC: 81 AN: 33474

American (AMR) AF: 0.00675 AC: 302 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00281 AC: 242 AN: 86252

European-Finnish (FIN) AF: 0.0178 AC: 934 AN: 52546

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0163 AC: 18176 AN: 1111926

Other (OTH) AF: 0.0108 AC: 655 AN: 60382

GnomAD4 genome AF: 0.00982 AC: 1494 AN: 152068 Hom.: 9 Cov.: 32 AF XY: 0.00979 AC XY: 728 AN XY: 74348

African (AFR) AF: 0.00253 AC: 105 AN: 41472

American (AMR) AF: 0.00903 AC: 138 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4816

European-Finnish (FIN) AF: 0.0172 AC: 182 AN: 10566

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1027 AN: 67970

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.0120 Hom.: 62

Bravo AF: 0.00870

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0141 AC: 121

ExAC AF: 0.00946 AC: 1148

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0143

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Cockayne syndrome (1)
-	-	1	COFS syndrome (1)
-	-	1	Macular degeneration (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.058
Sift	Benign	0.61	T
Sift4G	Benign	0.54	T
Polyphen		0.48	P
Vest4		0.33
MVP		0.75
MPC		0.17
ClinPred		0.032	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.16
Mutation Taster		=97/3	polymorphism

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: rs4253047; hg19: chr10-50732139; COSMIC: COSV63393791; COSMIC: COSV63393791;