chrX-72207230-G-A
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_017669.4(ERCC6L):c.1537C>T(p.Leu513Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,209,987 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., 3 hem., cov: 23)
Exomes 𝑓: 0.000010 ( 0 hom. 3 hem. )
Consequence
ERCC6L
NM_017669.4 missense
NM_017669.4 missense
Scores
1
8
8
Clinical Significance
Conservation
PhyloP100: 3.07
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.12910819).
BS2
High Hemizygotes in GnomAd4 at 3 gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ERCC6L | NM_017669.4 | c.1537C>T | p.Leu513Phe | missense_variant | 2/2 | ENST00000334463.4 | NP_060139.2 | |
ERCC6L | NM_001009954.3 | c.1168C>T | p.Leu390Phe | missense_variant | 3/3 | NP_001009954.1 | ||
PIN4 | NM_001170747.1 | c.312+10326G>A | intron_variant | NP_001164218.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ERCC6L | ENST00000334463.4 | c.1537C>T | p.Leu513Phe | missense_variant | 2/2 | 1 | NM_017669.4 | ENSP00000334675 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000179 AC: 20AN: 111810Hom.: 0 Cov.: 23 AF XY: 0.0000883 AC XY: 3AN XY: 33986
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GnomAD3 exomes AF: 0.0000492 AC: 9AN: 182969Hom.: 0 AF XY: 0.0000296 AC XY: 2AN XY: 67575
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GnomAD4 exome AF: 0.0000100 AC: 11AN: 1098125Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 3AN XY: 363489
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GnomAD4 genome AF: 0.000179 AC: 20AN: 111862Hom.: 0 Cov.: 23 AF XY: 0.0000881 AC XY: 3AN XY: 34048
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2023 | The c.1537C>T (p.L513F) alteration is located in exon 2 (coding exon 2) of the ERCC6L gene. This alteration results from a C to T substitution at nucleotide position 1537, causing the leucine (L) at amino acid position 513 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
D;D
Sift4G
Uncertain
D;D
Polyphen
1.0
.;D
Vest4
MVP
MPC
1.5
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at