X-74739447-A-T

Variant names:

• chrX-74739447-A-T
• NM_001008537.3:c.4509T>A
• NEXMIF p.Pro1503Pro

Variant summary

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

The NM_001008537.3(NEXMIF):​c.4509T>A​(p.Pro1503Pro) variant causes a synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P1503P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: NEXMIF NM_001008537.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.42
• Publications: 0 publications found

Genes affected

NEXMIF (HGNC:29433): (neurite extension and migration factor) An inversion on the X chromosome which disrupts this gene and a G-protein coupled purinergic receptor gene located in the pseudoautosomal region of the X chromosome has been linked to X linked cognitive disability.[provided by RefSeq, Mar 2009]

NEXMIF Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability, Cantagrel type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: REVEL computational evidence supports a deleterious effect, 0.754

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008537.3. 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
	NEXMIF	NM_001008537.3	MANE Select	c.4509T>A	p.Pro1503Pro	synonymous	Exon 4 of 4	NP_001008537.1	Q5QGS0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	ENST00000055682.12	TSL:1 MANE Select	c.4509T>A	p.Pro1503Pro	synonymous	Exon 4 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.4509T>A	p.Pro1503Pro	synonymous	Exon 4 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.*649T>A		3_prime_UTR	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.5
DANN	Benign	0.70
PhyloP100		6.4

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

hg19: chrX-73959282;