3-50341644-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015896.4(ZMYND10):c.1177C>T(p.Arg393Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ZMYND10 NM_015896.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38848132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMYND10	NM_015896.4	c.1177C>T	p.Arg393Cys	missense_variant	11/12	ENST00000231749.8
ZMYND10	NM_001308379.2	c.1162C>T	p.Arg388Cys	missense_variant	10/11
ZMYND10	XM_005265216.4	c.940C>T	p.Arg314Cys	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMYND10	ENST00000231749.8	c.1177C>T	p.Arg393Cys	missense_variant	11/12	1	NM_015896.4	P1
ZMYND10-AS1	ENST00000440013.1	n.123+416G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152258 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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251362 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74392

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: 0.0000941

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000501 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 28, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 393 of the ZMYND10 protein (p.Arg393Cys). This variant is present in population databases (rs587740488, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ZMYND10-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.98	D;D
Vest4		0.29
MutPred		0.53		Gain of catalytic residue at P392 (P = 0.0061);.;
MVP		0.22
MPC		0.22
ClinPred		0.57	D
GERP RS		4.6
Varity_R		0.27
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587740488; hg19: chr3-50379075; COSMIC: COSV51600730; COSMIC: COSV51600730;