X-72207574-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017669.4(ERCC6L):c.1193G>A(p.Arg398His) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,209,555 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 59 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00018 (0 hom. 56 hem.)
• Consequence: ERCC6L NM_017669.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 3.79

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21663523).
• BS2: High Hemizygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6L	NM_017669.4	c.1193G>A	p.Arg398His	missense_variant	2/2	ENST00000334463.4
ERCC6L	NM_001009954.3	c.824G>A	p.Arg275His	missense_variant	3/3
PIN4	NM_001170747.1	c.312+10670C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6L	ENST00000334463.4	c.1193G>A	p.Arg398His	missense_variant	2/2	1	NM_017669.4	P1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111490 Hom.: 0 Cov.: 22 AF XY: 0.0000891 AC XY: 3 AN XY: 33686

Gnomad AFR AF: 0.0000978

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: 0.000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000159 AC: 29 AN: 182925 Hom.: 0 AF XY: 0.000104 AC XY: 7 AN XY: 67519

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.000344

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000183 AC: 201 AN: 1098065 Hom.: 0 Cov.: 32 AF XY: 0.000154 AC XY: 56 AN XY: 363427

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111490 Hom.: 0 Cov.: 22 AF XY: 0.0000891 AC XY: 3 AN XY: 33686

Gnomad4 AFR AF: 0.0000978

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: 0.000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000197 Hom.: 11

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, 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	0.14
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.069	T;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.86	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	0.63	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.042	D;D
Sift4G	Uncertain	0.0070	D;T
Polyphen		0.65	.;P
Vest4		0.22
MVP		0.82
MPC		0.70
ClinPred		0.11	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.64

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

Other links and lift over

dbSNP: rs139313430; hg19: chrX-71427424;