X-71240948-G-C

Variant names:

• chrX-71240948-G-C
• rs140177072
• NM_201599.3:c.4081C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_201599.3(ZMYM3):​c.4081C>G​(p.Leu1361Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,098,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1361L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 5 hem.)
• Consequence: ZMYM3 NM_201599.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.104785174).
• BS2: High Hemizygotes in GnomAdExome4 at 5 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.4081C>G	p.Leu1361Val	missense	Exon 25 of 25	NP_963893.1	Q14202-1
	ZMYM3	NM_005096.3		c.4081C>G	p.Leu1361Val	missense	Exon 25 of 25	NP_005087.1	Q14202-1
	ZMYM3	NM_001171162.1		c.4045C>G	p.Leu1349Val	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.4081C>G	p.Leu1361Val	missense	Exon 25 of 25	ENSP00000322845.5	Q14202-1
	ZMYM3	ENST00000373998.5	TSL:1	c.4045C>G	p.Leu1349Val	missense	Exon 25 of 25	ENSP00000363110.1	Q14202-2
	ZMYM3	ENST00000373988.5	TSL:5	c.4087C>G	p.Leu1363Val	missense	Exon 25 of 25	ENSP00000363100.1	A6NHB5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000637 AC: 7 AN: 1098086 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363448

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000831 AC: 7 AN: 842020

Other (OTH) AF: 0.00 AC: 0 AN: 46093

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
PhyloP100		3.1
Varity_R		0.16
gMVP		0.83
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs140177072; hg19: chrX-70460798;