rs587777358

Variant names:

• chrX-71249610-G-A
• rs587777358
• NM_201599.3:c.1321C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_005096.3(ZMYM3):​c.1321C>T​(p.Arg441Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,849 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R441Q) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: ZMYM3 NM_005096.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 7.55
• Publications: 4 publications found

Genes affected

ZMYM3 (HGNC:13054): (zinc finger MYM-type containing 3) This gene is located on the X chromosome and is subject to X inactivation. It is highly conserved in vertebrates and most abundantly expressed in the brain. The encoded protein is a component of histone deacetylase-containing multiprotein complexes that function through modifying chromatin structure to keep genes silent. A chromosomal translocation (X;13) involving this gene is associated with X-linked cognitive disability. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2010]

ZMYM3 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, X-linked 112

  Inheritance: XL Classification: MODERATE Submitted by: G2P
• intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
• syndromic intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71249609-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1710149.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant X-71249610-G-A is Pathogenic according to our data. Variant chrX-71249610-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127192.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005096.3. 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
	ZMYM3	NM_201599.3	MANE Select	c.1321C>T	p.Arg441Trp	missense	Exon 7 of 25	NP_963893.1
	ZMYM3	NM_005096.3		c.1321C>T	p.Arg441Trp	missense	Exon 7 of 25	NP_005087.1
	ZMYM3	NM_001171162.1		c.1321C>T	p.Arg441Trp	missense	Exon 7 of 25	NP_001164633.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMYM3	ENST00000314425.9	TSL:1 MANE Select	c.1321C>T	p.Arg441Trp	missense	Exon 7 of 25	ENSP00000322845.5
	ZMYM3	ENST00000373998.5	TSL:1	c.1321C>T	p.Arg441Trp	missense	Exon 7 of 25	ENSP00000363110.1
	ZMYM3	ENST00000373981.5	TSL:1	c.1321C>T	p.Arg441Trp	missense	Exon 7 of 7	ENSP00000363093.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111849 Hom.: 0 Cov.: 23

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: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111849 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34019

African (AFR) AF: 0.00 AC: 0 AN: 30783

American (AMR) AF: 0.00 AC: 0 AN: 10570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2647

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53116

Other (OTH) AF: 0.00 AC: 0 AN: 1492

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder, X-linked 112 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.58		Loss of disorder (P = 0.052)
MVP		0.99
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.75
Mutation Taster		=1/99	disease causing

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: rs587777358; hg19: chrX-70469460; COSMIC: COSV58739216;