16-13926675-C-T

Variant names:

• chr16-13926675-C-T
• rs2020961
• NM_005236.3:c.503C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005236.3(ERCC4):​c.503C>T​(p.Ala168Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,946 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. A168G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00093 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.57
• Publications: 3 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: Genomics England PanelApp, G2P, ClinGen
• Fanconi anemia complementation group Q

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

LOC105371093 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04718116).
• BP6: Variant 16-13926675-C-T is Benign according to our data. Variant chr16-13926675-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 695963.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000932 (142/152286) while in subpopulation AFR AF = 0.00327 (136/41560). AF 95% confidence interval is 0.00282. There are 1 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.503C>T	p.Ala168Val	missense	Exon 3 of 11	NP_005227.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.503C>T	p.Ala168Val	missense	Exon 3 of 11	ENSP00000310520.7
	ERCC4	ENST00000575156.5	TSL:1	c.503C>T	p.Ala168Val	missense	Exon 3 of 6	ENSP00000459933.1
	ERCC4	ENST00000682617.1		c.641C>T	p.Ala214Val	missense	Exon 4 of 12	ENSP00000507912.1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000211 AC: 53 AN: 251458 AF XY: 0.000132

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 727142

African (AFR) AF: 0.00361 AC: 121 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111818

Other (OTH) AF: 0.000182 AC: 11 AN: 60390

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74470

African (AFR) AF: 0.00327 AC: 136 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.00119

ESP6500AA AF: 0.00455 AC: 20

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000305 AC: 37

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.26
Sift	Benign	0.14	T
Sift4G	Benign	1.0	T
Polyphen		0.059	B
Vest4		0.78
MVP		0.89
MPC		0.18
ClinPred		0.10	T
GERP RS		5.3
Varity_R		0.43
gMVP		0.86
Mutation Taster		=56/44	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: rs2020961; hg19: chr16-14020532;