10-49524073-G-C

Variant names:

• chr10-49524073-G-C
• rs121917902
• NM_000124.4:c.1357C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000124.4(ERCC6):​c.1357C>G​(p.Arg453Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08
• 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]

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33775735).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	NM_000124.4	MANE Select	c.1357C>G	p.Arg453Gly	missense	Exon 5 of 21	NP_000115.1
	ERCC6	NM_001277058.2	MANE Plus Clinical	c.1357C>G	p.Arg453Gly	missense	Exon 5 of 6	NP_001263987.1
	ERCC6	NM_001346440.2		c.1357C>G	p.Arg453Gly	missense	Exon 5 of 21	NP_001333369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.1357C>G	p.Arg453Gly	missense	Exon 5 of 21	ENSP00000348089.5
	ERCC6	ENST00000447839.7	TSL:2 MANE Plus Clinical	c.1357C>G	p.Arg453Gly	missense	Exon 5 of 6	ENSP00000387966.2
	ERCC6	ENST00000681659.1		c.1357C>G	p.Arg453Gly	missense	Exon 5 of 20	ENSP00000505631.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461566 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.047	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.1
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.11
Sift	Benign	0.090	T
Sift4G	Benign	0.12	T
Polyphen		0.91	P
Vest4		0.33
MutPred		0.41		Loss of ubiquitination at K448 (P = 0.0391)
MVP		0.84
MPC		0.29
ClinPred		0.89	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.21
Mutation Taster		=62/38	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: rs121917902; hg19: chr10-50732119;