chr20-47224390-C-T

Variant names:

• chr20-47224390-C-T
• NM_001281775.3:c.3183G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001281775.3(ZMYND8):​c.3183G>A​(p.Trp1061*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZMYND8 NM_001281775.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85
• Publications: 0 publications found

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]

ZMYND8 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281775.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMYND8	NM_001281775.3	MANE Select	c.3183G>A	p.Trp1061*	stop_gained	Exon 19 of 23	NP_001268704.1	Q9ULU4-7
	ZMYND8	NM_001363714.1		c.3204G>A	p.Trp1068*	stop_gained	Exon 19 of 23	NP_001350643.1	Q9ULU4-19
	ZMYND8	NM_001281773.3		c.3123G>A	p.Trp1041*	stop_gained	Exon 20 of 24	NP_001268702.1	Q9ULU4-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMYND8	ENST00000471951.7	TSL:1 MANE Select	c.3183G>A	p.Trp1061*	stop_gained	Exon 19 of 23	ENSP00000420095.2	Q9ULU4-7
	ZMYND8	ENST00000446994.6	TSL:1	c.3123G>A	p.Trp1041*	stop_gained	Exon 19 of 23	ENSP00000396725.3	Q9ULU4-11
	ZMYND8	ENST00000461685.5	TSL:1	c.3045G>A	p.Trp1015*	stop_gained	Exon 19 of 23	ENSP00000418210.1	Q9ULU4-13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.9
Vest4		0.47
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.6
Mutation Taster		=4/196	disease causing (fs/PTC)

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

Other links and lift over

hg19: chr20-45853043; COSMIC: COSV53696028;