rs148656966

Variant names:

• chrX-72205359-G-A
• rs148656966
• NM_017669.4:c.3408C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_017669.4(ERCC6L):​c.3408C>T​(p.Gly1136Gly) 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
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -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 GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6L	NM_017669.4	c.3408C>T	p.Gly1136Gly	synonymous_variant	Exon 2 of 2	ENST00000334463.4	NP_060139.2
ERCC6L	NM_001009954.3	c.3039C>T	p.Gly1013Gly	synonymous_variant	Exon 3 of 3		NP_001009954.1
PIN4	NM_001170747.1	c.312+8455G>A		intron_variant	Intron 3 of 3		NP_001164218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6L	ENST00000334463.4	c.3408C>T	p.Gly1136Gly	synonymous_variant	Exon 2 of 2	1	NM_017669.4	ENSP00000334675.3

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 42 AN: 112240 Hom.: 1 Cov.: 23

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

GnomAD2 exomes AF: 0.000426 AC: 78 AN: 183137 AF XY: 0.000473

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 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

African (AFR) AF: 0.000152 AC: 4 AN: 26399

American (AMR) AF: 0.000483 AC: 17 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.000406 AC: 22 AN: 54135

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40523

Middle Eastern (MID) AF: 0.00822 AC: 34 AN: 4135

European-Non Finnish (NFE) AF: 0.000403 AC: 339 AN: 841905

Other (OTH) AF: 0.000846 AC: 39 AN: 46089

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

African (AFR) AF: 0.000129 AC: 4 AN: 30962

American (AMR) AF: 0.000189 AC: 2 AN: 10583

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000563 AC: 30 AN: 53252

Other (OTH) AF: 0.00393 AC: 6 AN: 1525

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

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-4.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs148656966; hg19: chrX-71425209;