20-47236391-C-A

Position:

• chr20-47236391-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001281775.3(ZMYND8):​c.2791G>T​(p.Ala931Ser) 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. 15/21 in silico tools predict 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. A931T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZMYND8 NM_001281775.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

Genes affected

ZMYND8 (HGNC:9397): (zinc finger MYND-type containing 8) The protein encoded by this gene is a receptor for activated C-kinase (RACK) protein. The encoded protein has been shown to bind in vitro to activated protein kinase C beta I. In addition, this protein is a cutaneous T-cell lymphoma-associated antigen. Finally, the protein contains a bromodomain and two zinc fingers, and is thought to be a transcriptional regulator. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZMYND8. . Gene score misZ 4.0385 (greater than the threshold 3.09). Trascript score misZ 5.0127 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.081464946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMYND8	NM_001281775.3	c.2791G>T	p.Ala931Ser	missense_variant	16/23	ENST00000471951.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMYND8	ENST00000471951.7	c.2791G>T	p.Ala931Ser	missense_variant	16/23	1	NM_001281775.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZMYND8-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

The ZMYND8 c.2812G>T variant is predicted to result in the amino acid substitution p.Ala938Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.92	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;N;N;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.61	N;N;N;.;N;N;.;.;N;.;.;N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.17	T;T;T;.;T;T;.;.;T;.;.;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.17	B;.;B;.;.;.;.;.;.;P;P;B;.;P;.
Vest4		0.083
MutPred		0.10		Gain of phosphorylation at A911 (P = 0.042);.;.;Gain of phosphorylation at A911 (P = 0.042);Gain of phosphorylation at A911 (P = 0.042);Gain of phosphorylation at A911 (P = 0.042);.;.;.;.;.;.;.;.;.;
MVP		0.33
MPC		0.58
ClinPred		0.14	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.29

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: rs757483496; hg19: chr20-45865135;