NM_005236.3:c.1727G>C

Variant names:

• chr16-13935659-G-C
• rs1800068
• NM_005236.3:c.1727G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_005236.3(ERCC4):​c.1727G>C​(p.Arg576Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R576S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:2 O:1
• Conservation: PhyloP100: 6.07
• Publications: 11 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14403656).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000827 (126/152288) while in subpopulation AMR AF = 0.0019 (29/15296). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1727G>C	p.Arg576Thr	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.1727G>C	p.Arg576Thr	missense	Exon 8 of 11	ENSP00000310520.7	Q92889-1
	ERCC4	ENST00000682617.1		c.1865G>C	p.Arg622Thr	missense	Exon 9 of 12	ENSP00000507912.1	A0A804HKF9
	ERCC4	ENST00000389138.7	TSL:2	n.1004G>C		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000688 AC: 172 AN: 250108 AF XY: 0.000635

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00133 AC: 1942 AN: 1461836 Hom.: 1 Cov.: 32 AF XY: 0.00131 AC XY: 950 AN XY: 727216

African (AFR) AF: 0.000239 AC: 8 AN: 33466

American (AMR) AF: 0.00132 AC: 59 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00161 AC: 1793 AN: 1111988

Other (OTH) AF: 0.00129 AC: 78 AN: 60392

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74464

African (AFR) AF: 0.000361 AC: 15 AN: 41564

American (AMR) AF: 0.00190 AC: 29 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000871 Hom.: 0

Bravo AF: 0.00101

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000544 AC: 66

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	2	-	Fanconi anemia complementation group Q (2)
-	2	-	Xeroderma pigmentosum, group F (2)
-	-	1	Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (2)
-	1	-	Xeroderma pigmentosum (1)
-	1	-	Xeroderma pigmentosum, group F;C1970416:XFE progeroid syndrome;C3808988:Fanconi anemia complementation group Q (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.27
Sift	Benign	0.094	T
Sift4G	Benign	0.076	T
Polyphen		0.88	P
Vest4		0.78
MVP		0.79
MPC		0.14
ClinPred		0.090	T
GERP RS		5.3
Varity_R		0.28
gMVP		0.76
Mutation Taster		=83/17	polymorphism

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: rs1800068; hg19: chr16-14029516; COSMIC: COSV104606285;