chr3-50341463-C-T

Position:

• chr3-50341463-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015896.4(ZMYND10):​c.1270G>A​(p.Glu424Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: ZMYND10 NM_015896.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07609826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZMYND10	NM_015896.4	c.1270G>A	p.Glu424Lys	missense_variant	12/12	ENST00000231749.8	NP_056980.2
ZMYND10	NM_001308379.2	c.1255G>A	p.Glu419Lys	missense_variant	11/11		NP_001295308.1
ZMYND10	XM_005265216.4	c.1033G>A	p.Glu345Lys	missense_variant	11/11		XP_005265273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZMYND10	ENST00000231749.8	c.1270G>A	p.Glu424Lys	missense_variant	12/12	1	NM_015896.4	ENSP00000231749	P1
ZMYND10-AS1	ENST00000440013.1	n.123+235C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ZMYND10-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 424 of the ZMYND10 protein (p.Glu424Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.8	N;.
MutationTaster	Benign	0.92	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.069
Sift	Benign	0.61	T;T
Sift4G	Benign	0.88	T;T
Polyphen		0.0	B;B
Vest4		0.27
MutPred		0.41		Gain of MoRF binding (P = 0.0035);.;
MVP		0.055
MPC		0.18
ClinPred		0.48	T
GERP RS		2.4
Varity_R		0.081
gMVP		0.34

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: rs1575551902; hg19: chr3-50378894;