X-72205942-G-T

Position:

• chrX-72205942-G-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.2825C>A​(p.Pro942His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,420 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: ERCC6L NM_017669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0910

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=0.075807124).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC6L	NM_017669.4	c.2825C>A	p.Pro942His	missense_variant	2/2	ENST00000334463.4	NP_060139.2
ERCC6L	NM_001009954.3	c.2456C>A	p.Pro819His	missense_variant	3/3		NP_001009954.1
PIN4	NM_001170747.1	c.312+9038G>T		intron_variant			NP_001164218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6L	ENST00000334463.4	c.2825C>A	p.Pro942His	missense_variant	2/2	1	NM_017669.4	ENSP00000334675	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000274 AC: 5 AN: 182606 Hom.: 0 AF XY: 0.0000743 AC XY: 5 AN XY: 67250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000361

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097420 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 2 AN XY: 362842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000994

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.2825C>A (p.P942H) alteration is located in exon 2 (coding exon 2) of the ERCC6L gene. This alteration results from a C to A substitution at nucleotide position 2825, causing the proline (P) at amino acid position 942 to be replaced by a histidine (H). 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	Benign	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.022
DANN	Benign	0.25
DEOGEN2	Benign	0.020	T;T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.40	T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.2	.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.26
Sift	Benign	0.14	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.41	.;B
Vest4		0.080
MutPred		0.17		.;Loss of glycosylation at P942 (P = 0.0256);
MVP		0.50
MPC		0.69
ClinPred		0.060	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.20

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: rs770961426; hg19: chrX-71425792;