X-72205325-C-T

Position:

chrX-72205325-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 made for transcript

Verdict is Benign. Variant got -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. Variant chrX-72205325-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ERCC6L	NM_017669.4 linkuse as main transcript	c.3442G>A	p.Gly1148Arg	missense_variant	2/2	ENST00000334463.4	NP_060139.2
ERCC6L	NM_001009954.3 linkuse as main transcript	c.3073G>A	p.Gly1025Arg	missense_variant	3/3		NP_001009954.1
PIN4	NM_001170747.1 linkuse as main transcript	c.312+8421C>T		intron_variant			NP_001164218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6L	ENST00000334463.4 linkuse as main transcript	c.3442G>A	p.Gly1148Arg	missense_variant	2/2	1	NM_017669.4	ENSP00000334675	P1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

112203

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

AN XY:

34385

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

GnomAD3 exomes

AF:

0.000595

AC:

109

AN:

183141

Hom.:

AF XY:

0.000561

AC XY:

AN XY:

67697

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00375

Gnomad4 NFE exome

AF:

0.000386

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000347

AC:

AN:

112255

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

AN XY:

34447

show subpopulations

Gnomad4 AFR

AF:

0.0000646

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.000282

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000220

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

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

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

MutationTaster

Benign

1.0

N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over