dbSNP rs750358005: ERCC4:p.Met12Leu (chr16-13920199-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005236.3(ERCC4):c.34A>C(p.Met12Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,792 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M12I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.98

Publications

1 publications found

Variant links:

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

ERCC4 links:

LOC105371093 (HGNC:):

LOC105371093 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3 link	c.34A>C	p.Met12Leu	missense_variant	Exon 1 of 11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 link	c.34A>C	p.Met12Leu	missense_variant	Exon 1 of 11	1	NM_005236.3	ENSP00000310520.7		Q92889-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724092

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111880

Other (OTH)

AF:

0.00

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.063

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.085

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L

PhyloP100

8.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.72

.;N

REVEL

Benign

0.20

Sift

Benign

0.067

.;T

Sift4G

Benign

0.69

T;T

Polyphen

0.27

.;B

Vest4

0.60

MutPred

0.35

Loss of catalytic residue at M12 (P = 0.0959);Loss of catalytic residue at M12 (P = 0.0959);

MVP

0.81

MPC

0.086

ClinPred

0.83

GERP RS

5.1

PromoterAI

-0.71

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.77

gMVP

0.42

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over