NM_001008537.3:c.4459G>A

Variant names:

• chrX-74739497-C-T
• NM_001008537.3:c.4459G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008537.3(NEXMIF):​c.4459G>A​(p.Asp1487Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: NEXMIF NM_001008537.3 missense, splice_region
• Scores: Splicing: ADA: 0.004636
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21202248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.4459G>A	p.Asp1487Asn	missense_variant, splice_region_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.4459G>A	p.Asp1487Asn	missense_variant, splice_region_variant	Exon 4 of 4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.4459G>A	p.Asp1487Asn	missense_variant, splice_region_variant	Exon 4 of 5	1		ENSP00000480284.1
NEXMIF	ENST00000642681	c.*599G>A		3_prime_UTR_variant	Exon 3 of 3			ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1487 of the NEXMIF protein (p.Asp1487Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	.;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.16	N;.
REVEL	Benign	0.072
Sift	Benign	0.036	D;.
Sift4G	Uncertain	0.037	D;D
Polyphen		0.45	B;B
Vest4		0.23
MutPred		0.35		Gain of methylation at K1484 (P = 0.0805);Gain of methylation at K1484 (P = 0.0805);
MVP		0.35
MPC		0.22
ClinPred		0.46	T
GERP RS		5.3
Varity_R		0.15
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0046
dbscSNV1_RF	Benign	0.11
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-73959332; COSMIC: COSV104545572; COSMIC: COSV104545572;