X-72205325-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017669.4(ERCC6L):c.3442G>A(p.Gly1148Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,210,463 control chromosomes in the GnomAD database, including 1 homozygotes. There are 174 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 15 hem., cov: 23)

Exomes 𝑓: 0.00045 ( 1 hom. 159 hem. )

Consequence

ERCC6L
NM_017669.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:2

Conservation

PhyloP100: 0.572

Publications

9 publications found

Variant links:

Genes affected

ERCC6L (HGNC:20794): (ERCC excision repair 6 like, spindle assembly checkpoint helicase) This gene encodes a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF2) family of proteins, and contains a SNF2-like ATPase domain and a PICH family domain. One distinguishing feature of this SWI/SNF protein family member is that during interphase, the protein is excluded from the nucleus, and only associates with chromatin after the nuclear envelope has broken down. This protein is a DNA translocase that is thought to bind double-stranded DNA that is exposed to stretching forces, such as those exerted by the mitotic spindle. This protein associates with ribosomal DNA and ultra-fine DNA bridges (UFBs), fine structures that connect sister chromatids during anaphase at some sites such as fragile sites, telomeres and centromeres. This gene is required for the faithful segregation of sister chromatids during mitosis, and the ATPase activity of this protein required for the resolution of UFBs before cytokinesis. [provided by RefSeq, May 2017]

ERCC6L links:

PIN4 (HGNC:8992): (peptidylprolyl cis/trans isomerase, NIMA-interacting 4) This gene encodes a member of the parvulin subfamily of the peptidyl-prolyl cis/trans isomerase protein family. The encoded protein catalyzes the isomerization of peptidylprolyl bonds, and may play a role in the cell cycle, chromatin remodeling, and/or ribosome biogenesis. The encoded protein may play an additional role in the mitochondria. [provided by RefSeq, Dec 2009]

PIN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.013520628).

BP6

Variant X-72205325-C-T is Benign according to our data. Variant chrX-72205325-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1206029.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAd4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6L	NM_017669.4 link	c.3442G>A	p.Gly1148Arg	missense_variant	Exon 2 of 2	ENST00000334463.4	NP_060139.2	Q2NKX8
ERCC6L	NM_001009954.3 link	c.3073G>A	p.Gly1025Arg	missense_variant	Exon 3 of 3		NP_001009954.1
PIN4	NM_001170747.1 link	c.312+8421C>T		intron_variant	Intron 3 of 3		NP_001164218.1	Q9Y237-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6L	ENST00000334463.4 link	c.3442G>A	p.Gly1148Arg	missense_variant	Exon 2 of 2	1	NM_017669.4	ENSP00000334675.3		Q2NKX8

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

112203

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000648

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000282

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000595

AC:

109

AN:

183141

AF XY:

0.000561

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00450

Gnomad NFE exome

AF:

0.000429

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000445

AC:

489

AN:

1098208

Hom.:

Cov.:

AF XY:

0.000437

AC XY:

159

AN XY:

363576

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26401

American (AMR)

AF:

0.0000284

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00375

AC:

152

AN:

40525

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000386

AC:

325

AN:

842107

Other (OTH)

AF:

0.000217

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000347

AC:

AN:

112255

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

AN XY:

34447

show subpopulations

African (AFR)

AF:

0.0000646

AC:

AN:

30955

American (AMR)

AF:

0.00

AC:

AN:

10573

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2682

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

6143

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000282

AC:

AN:

53257

Other (OTH)

AF:

0.00

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000215

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.1

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.025

T;T

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.68

T;T

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.51

.;N

PhyloP100

0.57

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.17

Sift

Benign

0.12

T;T

Sift4G

Benign

0.085

T;T

Polyphen

0.0080

.;B

Vest4

0.030

MutPred

0.29

.;Loss of glycosylation at S1147 (P = 0.07);

MVP

0.45

MPC

0.66

ClinPred

0.028

GERP RS

-1.1

Varity_R

0.15

gMVP

0.24

Mutation Taster

=99/1

polymorphism (auto)

(source)

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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X-72205325-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over