X-72205359-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_017669.4(ERCC6L):c.3408C>T(p.Gly1136=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,210,259 control chromosomes in the GnomAD database, including 4 homozygotes. There are 169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00042 (3 hom. 160 hem.)
• Consequence: ERCC6L NM_017669.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.68

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-72205359-G-A is Benign according to our data. Variant chrX-72205359-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2660907.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.68 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6L	NM_017669.4	c.3408C>T	p.Gly1136=	synonymous_variant	2/2	ENST00000334463.4
ERCC6L	NM_001009954.3	c.3039C>T	p.Gly1013=	synonymous_variant	3/3
PIN4	NM_001170747.1	c.312+8455G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6L	ENST00000334463.4	c.3408C>T	p.Gly1136=	synonymous_variant	2/2	1	NM_017669.4	P1

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 42 AN: 112240 Hom.: 1 Cov.: 23 AF XY: 0.000262 AC XY: 9 AN XY: 34402

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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: 0.000563

Gnomad OTH AF: 0.00398

GnomAD3 exomes AF: 0.000426 AC: 78 AN: 183137 Hom.: 1 AF XY: 0.000473 AC XY: 32 AN XY: 67679

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000315

Gnomad FIN exome AF: 0.0000626

Gnomad NFE exome AF: 0.000600

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.000415 AC: 456 AN: 1097965 Hom.: 3 Cov.: 32 AF XY: 0.000440 AC XY: 160 AN XY: 363325

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000483

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000403

Gnomad4 OTH exome AF: 0.000846

GnomAD4 genome AF: 0.000374 AC: 42 AN: 112294 Hom.: 1 Cov.: 23 AF XY: 0.000261 AC XY: 9 AN XY: 34466

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000563

Gnomad4 OTH AF: 0.00393

Alfa AF: 0.00116 Hom.: 11

Bravo AF: 0.000589

EpiCase AF: 0.00109

EpiControl AF: 0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

ERCC6L: BP4, BP7, BS2; PIN4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.041
Dann	Benign	0.85

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: rs148656966; hg19: chrX-71425209;