NM_005236.3:c.1244G>C

Variant names:

• chr16-13935176-G-C
• rs1800067
• NM_005236.3:c.1244G>C
• ERCC4 p.Arg415Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_Supporting

The NM_005236.3(ERCC4):c.1244G>C (p.Arg415Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. 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). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R415G: Uncertain_significance (ClinVar VariationId 1006484, 1 star); p.R415Q: Benign/Likely_benign (ClinVar VariationId 134155, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 49 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

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>C p.Arg415Pro	missense	Exon 8 of 11	Prot: NP_005227.1 UniProt:

ERCC4 NM_005236.3

MANE Select

HGVSc / HGVSpc.1244G>Cp.Arg415Pro

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>C p.Arg415Pro	missense	Exon 8 of 11	Prot: ENSP00000310520.7 UniProt:
	ERCC4 ENST00000682617.1		c.1382G>C p.Arg461Pro	missense	Exon 9 of 12	Prot: ENSP00000507912.1 UniProt:
	ERCC4 ENST00000682826.1		n.*558G>C	3_prime_UTR	Exon 9 of 10	Prot: ENSP00000507274.1 UniProt:

ERCC4 ENST00000311895.8

TSL:1MANE Select

HGVSc / HGVSpc.1244G>Cp.Arg415Pro

Exon rankExon 8 of 11

missense

Prot: ENSP00000310520.7UniProt: Q92889-1

ERCC4 ENST00000682617.1

HGVSc / HGVSpc.1382G>Cp.Arg461Pro

Exon rankExon 9 of 12

missense

Prot: ENSP00000507912.1UniProt: A0A804HKF9

ERCC4 ENST00000682826.1

HGVSc / HGVSpn.*558G>C

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.89
GPN-Star LLR	N/A	-9.6
GPN-Star score	N/A	9.6
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Uncertain	2.8	M
PhyloP100	Pathogenic	9.6
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.95
VESM-3B	Benign	-14

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar