rs1800067

Variant names:

• chr16-13935176-G-A
• rs1800067
• NM_005236.3:c.1244G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-13935176-G-A
• chr16-13935176-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005236.3(ERCC4):​c.1244G>A​(p.Arg415Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,408 control chromosomes in the GnomAD database, including 4,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R415G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (326 hom., cov: 32)
  • Exomes 𝑓: 0.069 (4131 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 9.60
• Publications: 126 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: ClinGen, G2P, Genomics England PanelApp
• Fanconi anemia complementation group Q

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

ENSG00000262732 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030626655).
• BP6: Variant 16-13935176-G-A is Benign according to our data. Variant chr16-13935176-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	NM_005236.3	MANE Select	c.1244G>A	p.Arg415Gln	missense	Exon 8 of 11	NP_005227.1	Q92889-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.1244G>A	p.Arg415Gln	missense	Exon 8 of 11	ENSP00000310520.7	Q92889-1
	ERCC4	ENST00000682617.1		c.1382G>A	p.Arg461Gln	missense	Exon 9 of 12	ENSP00000507912.1	A0A804HKF9
	ERCC4	ENST00000389138.7	TSL:2	n.521G>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8111 AN: 152174 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0376

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0823

GnomAD2 exomes AF: 0.0561 AC: 14090 AN: 251016 AF XY: 0.0586

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.0452

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0765

Gnomad OTH exome AF: 0.0733

GnomAD4 exome AF: 0.0695 AC: 101541 AN: 1461116 Hom.: 4131 Cov.: 32 AF XY: 0.0695 AC XY: 50529 AN XY: 726926

African (AFR) AF: 0.0138 AC: 461 AN: 33470

American (AMR) AF: 0.0484 AC: 2164 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3064 AN: 26120

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0400 AC: 3453 AN: 86226

European-Finnish (FIN) AF: 0.0382 AC: 2039 AN: 53360

Middle Eastern (MID) AF: 0.133 AC: 769 AN: 5768

European-Non Finnish (NFE) AF: 0.0770 AC: 85576 AN: 1111362

Other (OTH) AF: 0.0664 AC: 4010 AN: 60388

GnomAD4 genome AF: 0.0532 AC: 8108 AN: 152292 Hom.: 326 Cov.: 32 AF XY: 0.0518 AC XY: 3856 AN XY: 74466

African (AFR) AF: 0.0150 AC: 624 AN: 41564

American (AMR) AF: 0.0660 AC: 1010 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0356 AC: 172 AN: 4832

European-Finnish (FIN) AF: 0.0376 AC: 399 AN: 10612

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5250 AN: 68010

Other (OTH) AF: 0.0810 AC: 171 AN: 2112

Alfa AF: 0.0712 Hom.: 2179

Bravo AF: 0.0539

TwinsUK AF: 0.0763 AC: 283

ALSPAC AF: 0.0810 AC: 312

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.0765 AC: 658

ExAC AF: 0.0556 AC: 6747

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0881

EpiControl AF: 0.0863

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (3)
-	-	2	Xeroderma pigmentosum, group F (2)
-	-	1	Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.27
MPC		0.46
ClinPred		0.037	T
GERP RS		5.8
Varity_R		0.67
gMVP		0.59
Mutation Taster		=86/14	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: rs1800067; hg19: chr16-14029033; COSMIC: COSV61311508; COSMIC: COSV61311508;