chr16-13935176-GA-CT

Variant names:

• chr16-13935176-GA-CT
• NM_005236.3:c.1244_1245delGAinsCT
• ERCC4 p.Arg415Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_005236.3(ERCC4):c.1244_1245delGAinsCT (p.Arg415Pro) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: 0 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.

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.1244_1245delGAinsCT p.Arg415Pro	missense	N/A	Prot: NP_005227.1 UniProt:

ERCC4 NM_005236.3

MANE Select

HGVSc / HGVSpc.1244_1245delGAinsCTp.Arg415Pro

Exon rankN/A

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.1244_1245delGAinsCT p.Arg415Pro	missense	N/A	Prot: ENSP00000310520.7 UniProt:
	ERCC4 ENST00000682617.1		c.1382_1383delGAinsCT p.Arg461Pro	missense	N/A	Prot: ENSP00000507912.1 UniProt:
	ERCC4 ENST00000682826.1		n.*558_*559delGAinsCT	3_prime_UTR	Exon 9 of 10	Prot: ENSP00000507274.1 UniProt:

ERCC4 ENST00000311895.8

TSL:1MANE Select

HGVSc / HGVSpc.1244_1245delGAinsCTp.Arg415Pro

Exon rankN/A

missense

Prot: ENSP00000310520.7UniProt: Q92889-1

ERCC4 ENST00000682617.1

HGVSc / HGVSpc.1382_1383delGAinsCTp.Arg461Pro

Exon rankN/A

missense

Prot: ENSP00000507912.1UniProt: A0A804HKF9

ERCC4 ENST00000682826.1

HGVSc / HGVSpn.*558_*559delGAinsCT

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

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.6

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr16-14029033;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar