rs3136215

Variant names:

• chr16-13946425-T-C
• rs3136215
• NM_005236.3:c.2018-1189T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005236.3(ERCC4):​c.2018-1189T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0354 in 152,292 control chromosomes in the GnomAD database, including 151 homozygotes. 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: 𝑓 0.035 (151 hom., cov: 33)
• Consequence: ERCC4 NM_005236.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.627
• Publications: 2 publications found

Genes affected

ERCC4 (HGNC:3436): (ERCC excision repair 4, endonuclease catalytic subunit) The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]

ERCC4 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• XFE progeroid syndrome

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005236.3. 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
	ERCC4	NM_005236.3	MANE Select	c.2018-1189T>C		intron	N/A	NP_005227.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.2018-1189T>C		intron	N/A	ENSP00000310520.7
	ERCC4	ENST00000682617.1		c.2156-1189T>C		intron	N/A	ENSP00000507912.1
	ERCC4	ENST00000389138.7	TSL:2	n.1295-1189T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5397 AN: 152174 Hom.: 151 Cov.: 33

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0339

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

GnomAD4 genome AF: 0.0354 AC: 5395 AN: 152292 Hom.: 151 Cov.: 33 AF XY: 0.0324 AC XY: 2411 AN XY: 74476

African (AFR) AF: 0.00914 AC: 380 AN: 41556

American (AMR) AF: 0.0333 AC: 510 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 218 AN: 3470

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

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4832

European-Finnish (FIN) AF: 0.0279 AC: 296 AN: 10616

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0556 AC: 3780 AN: 68014

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0437 Hom.: 17

Bravo AF: 0.0353

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.3
DANN	Benign	0.60
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3136215; hg19: chr16-14040282;