X-72205325-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 0.572

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 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 GnomAd at 15 gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 39 AN: 112203 Hom.: 0 Cov.: 23 AF XY: 0.000436 AC XY: 15 AN XY: 34385

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.: 0 AF XY: 0.000561 AC XY: 38 AN XY: 67697

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.: 1 Cov.: 32 AF XY: 0.000437 AC XY: 159 AN XY: 363576

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: 39 AN: 112255 Hom.: 0 Cov.: 23 AF XY: 0.000435 AC XY: 15 AN XY: 34447

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.: 6

Bravo AF: 0.000166

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

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	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	1.1
Dann	Benign	0.75
DEOGEN2	Benign	0.025	T;T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs78660817; hg19: chrX-71425175; COSMIC: COSV57819844;