20-47210799-G-A

Variant names:

• chr20-47210799-G-A
• rs142922966
• NM_001281775.3:c.3667C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001281775.3(ZMYND8):​c.3667C>T​(p.Leu1223Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ZMYND8 NM_001281775.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0220
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04437548).
• BS2: High AC in GnomAd4 at 16 AD gene.

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.3667C>T	p.Leu1223Phe	missense	Exon 23 of 23	NP_001268704.1	Q9ULU4-7
	ZMYND8	NM_001363714.1		c.3688C>T	p.Leu1230Phe	missense	Exon 23 of 23	NP_001350643.1	Q9ULU4-19
	ZMYND8	NM_001281773.3		c.3607C>T	p.Leu1203Phe	missense	Exon 24 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.3667C>T	p.Leu1223Phe	missense	Exon 23 of 23	ENSP00000420095.2	Q9ULU4-7
	ZMYND8	ENST00000446994.6	TSL:1	c.3607C>T	p.Leu1203Phe	missense	Exon 23 of 23	ENSP00000396725.3	Q9ULU4-11
	ZMYND8	ENST00000461685.5	TSL:1	c.3529C>T	p.Leu1177Phe	missense	Exon 23 of 23	ENSP00000418210.1	Q9ULU4-13

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000191

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000191 AC: 48 AN: 251490 AF XY: 0.000213

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000134 AC: 196 AN: 1461882 Hom.: 0 Cov.: 30 AF XY: 0.000157 AC XY: 114 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000156 AC: 173 AN: 1112008

Other (OTH) AF: 0.0000828 AC: 5 AN: 60394

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74416

African (AFR) AF: 0.00 AC: 0 AN: 41530

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68012

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.022
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.22	T
Polyphen		0.22	B
Vest4		0.082
MVP		0.48
MPC		0.61
ClinPred		0.055	T
GERP RS		-7.8
Varity_R		0.098
gMVP		0.049
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs142922966; hg19: chr20-45839444;