X-72205067-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017669.4(ERCC6L):c.3700C>T(p.Pro1234Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000736 in 1,208,775 control chromosomes in the GnomAD database, including 1 homozygotes. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000064 ( 1 hom. 19 hem. )

Consequence

ERCC6L
NM_017669.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.66

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030458182).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6L	NM_017669.4 link	c.3700C>T	p.Pro1234Ser	missense_variant	Exon 2 of 2	ENST00000334463.4	NP_060139.2	Q2NKX8
ERCC6L	NM_001009954.3 link	c.3331C>T	p.Pro1111Ser	missense_variant	Exon 3 of 3		NP_001009954.1
PIN4	NM_001170747.1 link	c.312+8163G>A		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.3700C>T	p.Pro1234Ser	missense_variant	Exon 2 of 2	1	NM_017669.4	ENSP00000334675.3		Q2NKX8

Frequencies

GnomAD3 genomes

AF:

0.000170

AC:

AN:

112003

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34185

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00171

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000238

AC:

AN:

180716

Hom.:

AF XY:

0.000168

AC XY:

AN XY:

65368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00152

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000449

GnomAD4 exome

AF:

0.0000638

AC:

AN:

1096720

Hom.:

Cov.:

AF XY:

0.0000525

AC XY:

AN XY:

362232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000869

GnomAD4 genome

AF:

0.000170

AC:

AN:

112055

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34247

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00171

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000189

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3700C>T (p.P1234S) alteration is located in exon 2 (coding exon 2) of the ERCC6L gene. This alteration results from a C to T substitution at nucleotide position 3700, causing the proline (P) at amino acid position 1234 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

0.68

.;P

Vest4

0.19

MutPred

0.39

.;Gain of phosphorylation at P1234 (P = 0.0921);

MVP

0.70

MPC

0.76

ClinPred

0.22

GERP RS

4.6

Varity_R

0.55

gMVP

0.60

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