X-71241095-G-A

Variant names:

• chrX-71241095-G-A
• rs2029922009
• NM_201599.3:c.3934C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_201599.3(ZMYM3):​c.3934C>T​(p.Arg1312Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZMYM3 NM_201599.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201599.3. 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.3934C>T	p.Arg1312Trp	missense	Exon 25 of 25	NP_963893.1	Q14202-1
	ZMYM3	NM_005096.3		c.3934C>T	p.Arg1312Trp	missense	Exon 25 of 25	NP_005087.1	Q14202-1
	ZMYM3	NM_001171162.1		c.3898C>T	p.Arg1300Trp	missense	Exon 25 of 25	NP_001164633.1	Q14202-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMYM3	ENST00000314425.9	TSL:1 MANE Select	c.3934C>T	p.Arg1312Trp	missense	Exon 25 of 25	ENSP00000322845.5	Q14202-1
	ZMYM3	ENST00000373998.5	TSL:1	c.3898C>T	p.Arg1300Trp	missense	Exon 25 of 25	ENSP00000363110.1	Q14202-2
	ZMYM3	ENST00000373988.5	TSL:5	c.3940C>T	p.Arg1314Trp	missense	Exon 25 of 25	ENSP00000363100.1	A6NHB5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.55		Loss of disorder (P = 0.0328)
MVP		0.51
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.80
gMVP		0.97
Mutation Taster		=87/13	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: rs2029922009; hg19: chrX-70460945;