X-74739491-C-A

Variant names:

• chrX-74739491-C-A
• rs751841142
• NM_001008537.3:c.4465G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008537.3(NEXMIF):​c.4465G>T​(p.Asp1489Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000931 in 1,074,331 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1489N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.128
• 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: Labcorp Genetics (formerly Invitae), Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19068652).

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.4465G>T	p.Asp1489Tyr	missense	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.4465G>T	p.Asp1489Tyr	missense	Exon 4 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.4465G>T	p.Asp1489Tyr	missense	Exon 4 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.*605G>T		3_prime_UTR	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.31e-7 AC: 1 AN: 1074331 Hom.: 0 Cov.: 25 AF XY: 0.00000293 AC XY: 1 AN XY: 341813

African (AFR) AF: 0.00 AC: 0 AN: 25781

American (AMR) AF: 0.00 AC: 0 AN: 33681

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19046

East Asian (EAS) AF: 0.00 AC: 0 AN: 29787

South Asian (SAS) AF: 0.00 AC: 0 AN: 51245

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4059

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825174

Other (OTH) AF: 0.0000221 AC: 1 AN: 45230

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.13
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.019	D
Polyphen		0.95	P
Vest4		0.48
MutPred		0.31		Loss of disorder (P = 0.0519)
MVP		0.21
MPC		0.55
ClinPred		0.67	D
GERP RS		0.63
Varity_R		0.21
gMVP		0.53
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs751841142; hg19: chrX-73959326;