X-71240964-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_201599.3(ZMYM3):c.4065C>T(p.Arg1355=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 96662.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chrX-71240964-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.962 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMYM3	NM_201599.3	c.4065C>T	p.Arg1355=	synonymous_variant	25/25	ENST00000314425.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMYM3	ENST00000314425.9	c.4065C>T	p.Arg1355=	synonymous_variant	25/25	1	NM_201599.3	P4

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 112 AN: 111313 Hom.: 0 Cov.: 22 AF XY: 0.000716 AC XY: 24 AN XY: 33531

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

GnomAD3 exomes AF: 0.000974 AC: 178 AN: 182730 Hom.: 0 AF XY: 0.000950 AC XY: 64 AN XY: 67354

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 SAS exome AF: 0.000262

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

Gnomad4 AFR exome AF: 0.0000757

Gnomad4 AMR exome AF: 0.000597

Gnomad4 ASJ exome AF: 0.00294

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.00165

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

Gnomad4 AFR AF: 0.000163

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00416

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00142

Gnomad4 OTH AF: 0.00263

Alfa AF: 0.00145 Hom.: 12

Bravo AF: 0.00116

EpiCase AF: 0.00295

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.9
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs142437272; hg19: chrX-70460814;