chrX-72207313-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_017669.4(ERCC6L):​c.1454C>T​(p.Ser485Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000289 in 1,208,985 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 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 0.000036 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.000028 ( 0 hom. 8 hem. )

Consequence

ERCC6L
NM_017669.4 missense

Scores

1
14
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.02
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.41971076).
BS2
High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERCC6LNM_017669.4 linkuse as main transcriptc.1454C>T p.Ser485Leu missense_variant 2/2 ENST00000334463.4 NP_060139.2
ERCC6LNM_001009954.3 linkuse as main transcriptc.1085C>T p.Ser362Leu missense_variant 3/3 NP_001009954.1
PIN4NM_001170747.1 linkuse as main transcriptc.312+10409G>A intron_variant NP_001164218.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERCC6LENST00000334463.4 linkuse as main transcriptc.1454C>T p.Ser485Leu missense_variant 2/21 NM_017669.4 ENSP00000334675 P1

Frequencies

GnomAD3 genomes
AF:
0.0000358
AC:
4
AN:
111880
Hom.:
0
Cov.:
23
AF XY:
0.0000587
AC XY:
2
AN XY:
34054
show subpopulations
Gnomad AFR
AF:
0.0000649
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.000663
GnomAD3 exomes
AF:
0.0000220
AC:
4
AN:
182174
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
66990
show subpopulations
Gnomad AFR exome
AF:
0.0000766
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:
0.00
Gnomad NFE exome
AF:
0.0000369
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000283
AC:
31
AN:
1097105
Hom.:
0
Cov.:
32
AF XY:
0.0000221
AC XY:
8
AN XY:
362573
show subpopulations
Gnomad4 AFR exome
AF:
0.0000758
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000250
Gnomad4 OTH exome
AF:
0.0000869
GnomAD4 genome
AF:
0.0000358
AC:
4
AN:
111880
Hom.:
0
Cov.:
23
AF XY:
0.0000587
AC XY:
2
AN XY:
34054
show subpopulations
Gnomad4 AFR
AF:
0.0000649
Gnomad4 AMR
AF:
0.00
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:
0.000663
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 26, 2022The c.1454C>T (p.S485L) 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 1454, causing the serine (S) at amino acid position 485 to be replaced by a leucine (L). 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
Uncertain
0.44
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
0.010
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.56
D;D
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.42
T;T
MetaSVM
Uncertain
0.63
D
MutationAssessor
Uncertain
2.3
.;M
MutationTaster
Benign
0.92
D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-5.3
D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.011
D;D
Polyphen
1.0
.;D
Vest4
0.30
MutPred
0.55
.;Loss of catalytic residue at Q487 (P = 0.0709);
MVP
0.92
MPC
0.69
ClinPred
0.68
D
GERP RS
4.0
Varity_R
0.45
gMVP
0.77

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.

Other links and lift over

dbSNP: rs762834270; hg19: chrX-71427163; COSMIC: COSV57822458; API