ERCC4 p.Arg415Gln

Variant names:

• chr16-13935176-G-A
• rs1800067
• NM_005236.3:c.1244G>A
• ERCC4 p.Arg415Gln

Your query was ambiguous. Multiple possible variants found:

• chr16-13935176-G-A
• chr16-13935176-GA-AG

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP6_Strong

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 cumulative frequency of 0.068 (AC=109,649) in the gnomAD database across 1,613,408 control chromosomes, including 4,457 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.126. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.60). Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R415G: Uncertain_significance (ClinVar VariationId 1006484, 1 star) This exact variant is curated in the UniProt human variants database 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:9 O:1
• Conservation: PhyloP100: 9.60
• Publications: 130 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: PanelApp Australia, ClinGen, Genomics England PanelApp, G2P
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, 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:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1255 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005236.3. You can select a different transcript below to see updated classification 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	Prot: NP_005227.1 UniProt:

ERCC4 NM_005236.3

MANE Select

HGVSc / HGVSpc.1244G>Ap.Arg415Gln

Exon rankExon 8 of 11

missense

Prot: NP_005227.1UniProt: A0A1W1GSK9Q92889-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ERCC4 ENST00000311895.8	TSL:1MANE Select	c.1244G>A p.Arg415Gln	missense	Exon 8 of 11	Prot: ENSP00000310520.7 UniProt:
	ERCC4 ENST00000682617.1		c.1382G>A p.Arg461Gln	missense	Exon 9 of 12	Prot: ENSP00000507912.1 UniProt:
	ERCC4 ENST00000682826.1		n.*558G>A	3_prime_UTR	Exon 9 of 10	Prot: ENSP00000507274.1 UniProt:

ERCC4 ENST00000311895.8

TSL:1MANE Select

HGVSc / HGVSpc.1244G>Ap.Arg415Gln

Exon rankExon 8 of 11

missense

Prot: ENSP00000310520.7UniProt: Q92889-1

ERCC4 ENST00000682617.1

HGVSc / HGVSpc.1382G>Ap.Arg461Gln

Exon rankExon 9 of 12

missense

Prot: ENSP00000507912.1UniProt: A0A804HKF9

ERCC4 ENST00000682826.1

HGVSc / HGVSpn.*558G>A

Exon rankExon 9 of 10

3_prime_UTR

Prot: ENSP00000507274.1UniProt: A0A804HIY2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0533	AC:8111	Hom:326	AN:152174	Cov:32
GnomAD2 exomes	AF: 0.0561	AC:14090	Hom:	AN:251016	Cov:
GnomAD4 exome	AF: 0.0695	AC:101541	Hom:4131	AN:1461116	Cov:32
GnomAD4 genome	AF: 0.0532	AC:8108	Hom:326	AN:152292	Cov:32
TOPMed (Bravo)	AF: 0.0539	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0704	AC:56288	Hom:2305	AN:799464	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0722	AC:169	Hom:8	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000591	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0433	AC:13	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0548	AC:712	Hom:	AN:12994	Cov:
GenomeAsia100K	AF: 0.0160	AC:55	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.201	AC:403	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000730	AC:9	Hom:0	AN:122736	Cov:
Turkish Variome	AF: 0.0850	AC:571	Hom:28	AN:6720	Cov:
UK10K	AF: 0.0787	AC:595	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000558	AC:5	Hom:0	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0680 *	755	11106	0.0654 *	1151	17612
BipEx(Bipolar disorder (including schizoaffective))	0.0700	1989	28418	0.0682	1967	28840
Epi25(Epilepsy)	0.0688	2885	41958	0.0663	4431	66882
SCHEMA(Schizophrenia)	0.0613	7706	125678	0.0746	15077	202022

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (4)
-	-	2	Xeroderma pigmentosum, group F (2)
-	-	1	Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
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
GPN-Star LLR	N/A	-6.5
GPN-Star score	N/A	6.5
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.68	T
Mutation Taster	N/A	86/14	polymorphism (auto)
MutationAssessor	Uncertain	2.8	M
PhyloP100	Pathogenic	9.6
popEVE	Benign	-2.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Varity_R	N/A	0.67
VESM-3B	Benign	-9.4

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1800067;

hg19: chr16-14029033;

COSMIC: COSV61311508;

COSMIC: COSV61311508;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar