rs138815960
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000442887.1(ZMYND10):c.-38+2T>G variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,609,790 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00026 ( 1 hom. )
Consequence
ZMYND10
ENST00000442887.1 splice_donor
ENST00000442887.1 splice_donor
Scores
2
13
4
Clinical Significance
Conservation
PhyloP100: 3.38
Genes affected
ZMYND10 (HGNC:19412): (zinc finger MYND-type containing 10) This gene encodes a protein containing a MYND-type zinc finger domain that likely functions in assembly of the dynein motor. Mutations in this gene can cause primary ciliary dyskinesia. This gene is also considered a tumor suppressor gene and is often mutated, deleted, or hypermethylated and silenced in cancer cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease,
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-50345533-A-C is Pathogenic according to our data. Variant chr3-50345533-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 66021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-50345533-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZMYND10 | NM_015896.4 | c.47T>G | p.Val16Gly | missense_variant | 1/12 | ENST00000231749.8 | |
ZMYND10 | NM_001308379.2 | c.47T>G | p.Val16Gly | missense_variant | 1/11 | ||
ZMYND10 | XM_005265216.4 | c.-82T>G | 5_prime_UTR_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZMYND10 | ENST00000231749.8 | c.47T>G | p.Val16Gly | missense_variant | 1/12 | 1 | NM_015896.4 | P1 | |
ZMYND10-AS1 | ENST00000440013.1 | n.124-38A>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000270 AC: 65AN: 241060Hom.: 0 AF XY: 0.000259 AC XY: 34AN XY: 131386
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GnomAD4 exome AF: 0.000263 AC: 383AN: 1457588Hom.: 1 Cov.: 31 AF XY: 0.000269 AC XY: 195AN XY: 724694
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GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74356
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 22 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Apr 07, 2023 | This ZMYND10 missense variant has been reported to occur in the homozygous or compound heterozygous state in unrelated individuals and families with primary ciliary dyskinesia. This variant (rs138815960) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 67/272444 total alleles; 0.025%; no homozygotes), and has been reported in ClinVar6 (Variation ID 66021). Two bioinformatic tools queried predict that this substitution would be damaging, and the valine residue at this position is evolutionarily conserved across many of the species assessed. We consider c.47T>G;p.Val16Gly in ZMYND10 to be pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 25, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 09, 2023 | - - |
Primary ciliary dyskinesia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 16 of the ZMYND10 protein (p.Val16Gly). This variant is present in population databases (rs138815960, gnomAD 0.05%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23891469, 23891471). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ZMYND10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ZMYND10 function (PMID: 23891471). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre | Dec 11, 2023 | ACMG: PP5, PM2, PM3. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 66021) - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 21, 2019 | - - |
Kartagener syndrome Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
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