X-74739456-C-A

Variant names:

• chrX-74739456-C-A
• NM_001008537.3:c.4500G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001008537.3(NEXMIF):​c.4500G>T​(p.Trp1500Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27558157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.4500G>T	p.Trp1500Cys	missense_variant	Exon 4 of 4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.4500G>T	p.Trp1500Cys	missense_variant	Exon 4 of 4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.4500G>T	p.Trp1500Cys	missense_variant	Exon 4 of 5	1		ENSP00000480284.1
NEXMIF	ENST00000642681	c.*640G>T		3_prime_UTR_variant	Exon 3 of 3			ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.033	T;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.1	N;.
REVEL	Benign	0.12
Sift	Uncertain	0.018	D;.
Sift4G	Benign	0.087	T;T
Polyphen		0.97	D;D
Vest4		0.36
MutPred		0.56		Loss of catalytic residue at P1503 (P = 0.1951);Loss of catalytic residue at P1503 (P = 0.1951);
MVP		0.068
MPC		0.81
ClinPred		0.66	D
GERP RS		3.7
Varity_R		0.29
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-73959291;