3-50341442-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015896.4(ZMYND10):c.1291G>A(p.Val431Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: ZMYND10 NM_015896.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.180

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]

ZMYND10-AS1 (HGNC:40890): (ZMYND10 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04663223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMYND10	NM_015896.4	c.1291G>A	p.Val431Ile	missense_variant	12/12	ENST00000231749.8
ZMYND10	NM_001308379.2	c.1276G>A	p.Val426Ile	missense_variant	11/11
ZMYND10	XM_005265216.4	c.1054G>A	p.Val352Ile	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMYND10	ENST00000231749.8	c.1291G>A	p.Val431Ile	missense_variant	12/12	1	NM_015896.4	P1
ZMYND10-AS1	ENST00000440013.1	n.123+214C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251454 Hom.: 1 AF XY: 0.0000957 AC XY: 13 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 163 AN: 1461878 Hom.: 1 Cov.: 31 AF XY: 0.000102 AC XY: 74 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 26, 2023	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 431 of the ZMYND10 protein (p.Val431Ile). This variant is present in population databases (rs201258677, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with ZMYND10-related conditions. ClinVar contains an entry for this variant (Variation ID: 961694). 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 not expected to disrupt ZMYND10 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Feb 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.072	T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.62	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.020
Sift	Benign	0.20	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.029	B;B
Vest4		0.11
MVP		0.014
MPC		0.13
ClinPred		0.057	T
GERP RS		1.9
Varity_R		0.069
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201258677; hg19: chr3-50378873;