NM_005236.3:c.1904+2986T>C

Variant names:

• chr16-13940844-T-C
• rs3136189
• NM_005236.3:c.1904+2986T>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.1904+2986T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 152,114 control chromosomes in the GnomAD database, including 5,081 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 0.25 (5081 hom., cov: 32)
• Consequence: ERCC4 NM_005236.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 12 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=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.281 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.1904+2986T>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.1904+2986T>C		intron	N/A	ENSP00000310520.7
	ERCC4	ENST00000682617.1		c.2042+2986T>C		intron	N/A	ENSP00000507912.1
	ERCC4	ENST00000389138.7	TSL:2	n.1181+2986T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38392 AN: 151996 Hom.: 5072 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.292

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

GnomAD4 genome AF: 0.253 AC: 38430 AN: 152114 Hom.: 5081 Cov.: 32 AF XY: 0.251 AC XY: 18644 AN XY: 74372

African (AFR) AF: 0.193 AC: 8022 AN: 41472

American (AMR) AF: 0.250 AC: 3826 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1028 AN: 3464

East Asian (EAS) AF: 0.249 AC: 1286 AN: 5166

South Asian (SAS) AF: 0.293 AC: 1413 AN: 4818

European-Finnish (FIN) AF: 0.235 AC: 2496 AN: 10602

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19352 AN: 67984

Other (OTH) AF: 0.294 AC: 621 AN: 2114

Alfa AF: 0.274 Hom.: 7808

Bravo AF: 0.251

Asia WGS AF: 0.294 AC: 1024 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.89
PhyloP100		0.076
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: rs3136189; hg19: chr16-14034701;