rs757166092

Variant names:

• chrX-71250166-T-C
• rs757166092
• NM_201599.3:c.1111A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_201599.3(ZMYM3):​c.1111A>G​(p.Thr371Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,083,028 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 2 hem.)
• Consequence: ZMYM3 NM_201599.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.51
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18664512).
• BP6: Variant X-71250166-T-C is Benign according to our data. Variant chrX-71250166-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 521989.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.1111A>G	p.Thr371Ala	missense	Exon 6 of 25	NP_963893.1	Q14202-1
	ZMYM3	NM_005096.3		c.1111A>G	p.Thr371Ala	missense	Exon 6 of 25	NP_005087.1	Q14202-1
	ZMYM3	NM_001171162.1		c.1111A>G	p.Thr371Ala	missense	Exon 6 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.1111A>G	p.Thr371Ala	missense	Exon 6 of 25	ENSP00000322845.5	Q14202-1
	ZMYM3	ENST00000373998.5	TSL:1	c.1111A>G	p.Thr371Ala	missense	Exon 6 of 25	ENSP00000363110.1	Q14202-2
	ZMYM3	ENST00000373981.5	TSL:1	c.1111A>G	p.Thr371Ala	missense	Exon 6 of 7	ENSP00000363093.1	Q14202-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000615 AC: 1 AN: 162716 AF XY: 0.0000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000136

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 3 AN: 1083028 Hom.: 0 Cov.: 32 AF XY: 0.00000569 AC XY: 2 AN XY: 351264

African (AFR) AF: 0.00 AC: 0 AN: 25910

American (AMR) AF: 0.00 AC: 0 AN: 32822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18415

East Asian (EAS) AF: 0.00 AC: 0 AN: 30026

South Asian (SAS) AF: 0.00 AC: 0 AN: 50793

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40071

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4043

European-Non Finnish (NFE) AF: 0.00000359 AC: 3 AN: 835519

Other (OTH) AF: 0.00 AC: 0 AN: 45429

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.088
Sift	Benign	0.098	T
Sift4G	Benign	0.29	T
Polyphen		0.20	B
Vest4		0.28
MutPred		0.66		Loss of disorder (P = 0.1542)
MVP		0.19
ClinPred		0.38	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.50
Mutation Taster		=84/16	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: rs757166092; hg19: chrX-70470016;