chrX-71240964-G-A

Variant names:

• chrX-71240964-G-A
• rs142437272
• NM_201599.3:c.4065C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_201599.3(ZMYM3):​c.4065C>T​(p.Arg1355Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,209,541 control chromosomes in the GnomAD database, including 3 homozygotes. There are 433 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 24 hem., cov: 22)
  • Exomes 𝑓: 0.0013 (3 hom. 409 hem.)
• Consequence: ZMYM3 NM_201599.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.962
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-71240964-G-A is Benign according to our data. Variant chrX-71240964-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96662.
• BP7: Synonymous conserved (PhyloP=-0.962 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 24 XL gene

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.4065C>T	p.Arg1355Arg	synonymous	Exon 25 of 25	NP_963893.1	Q14202-1
	ZMYM3	NM_005096.3		c.4065C>T	p.Arg1355Arg	synonymous	Exon 25 of 25	NP_005087.1	Q14202-1
	ZMYM3	NM_001171162.1		c.4029C>T	p.Arg1343Arg	synonymous	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.4065C>T	p.Arg1355Arg	synonymous	Exon 25 of 25	ENSP00000322845.5	Q14202-1
	ZMYM3	ENST00000373998.5	TSL:1	c.4029C>T	p.Arg1343Arg	synonymous	Exon 25 of 25	ENSP00000363110.1	Q14202-2
	ZMYM3	ENST00000373988.5	TSL:5	c.4071C>T	p.Arg1357Arg	synonymous	Exon 25 of 25	ENSP00000363100.1	A6NHB5

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 112 AN: 111313 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00416

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.00142

Gnomad OTH AF: 0.00266

GnomAD2 exomes AF: 0.000974 AC: 178 AN: 182730 AF XY: 0.000950

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00255

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00128 AC: 1409 AN: 1098176 Hom.: 3 Cov.: 31 AF XY: 0.00113 AC XY: 409 AN XY: 363534

African (AFR) AF: 0.0000757 AC: 2 AN: 26403

American (AMR) AF: 0.000597 AC: 21 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00294 AC: 57 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.000499 AC: 27 AN: 54147

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40517

Middle Eastern (MID) AF: 0.00701 AC: 29 AN: 4136

European-Non Finnish (NFE) AF: 0.00142 AC: 1196 AN: 842093

Other (OTH) AF: 0.00165 AC: 76 AN: 46095

GnomAD4 genome AF: 0.000997 AC: 111 AN: 111365 Hom.: 0 Cov.: 22 AF XY: 0.000714 AC XY: 24 AN XY: 33593

African (AFR) AF: 0.000163 AC: 5 AN: 30675

American (AMR) AF: 0.00124 AC: 13 AN: 10472

Ashkenazi Jewish (ASJ) AF: 0.00416 AC: 11 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2643

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6025

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.00142 AC: 75 AN: 52962

Other (OTH) AF: 0.00263 AC: 4 AN: 1520

Alfa AF: 0.00145 Hom.: 12

Bravo AF: 0.00116

EpiCase AF: 0.00295

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.73
PhyloP100		-0.96
Mutation Taster		=100/0	polymorphism (auto)

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: rs142437272; hg19: chrX-70460814;