X-74739496-T-C

Variant summary

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

The NM_001008537.3(NEXMIF):c.4460A>G(p.Asp1487Gly) variant causes a missense, splice region 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. 13/19 in silico tools predict a benign outcome for this variant. 1/1 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

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=0.077084094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.4460A>G	p.Asp1487Gly	missense_variant, splice_region_variant	4/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.4460A>G	p.Asp1487Gly	missense_variant, splice_region_variant	4/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.4460A>G	p.Asp1487Gly	missense_variant, splice_region_variant	4/5	1		P1
NEXMIF	ENST00000642681.2	c.*600A>G		3_prime_UTR_variant	3/3

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 08, 2019

This sequence change replaces aspartic acid with glycine at codon 1487 of the NEXMIF protein (p.Asp1487Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NEXMIF-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	0.086
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.059	T;T
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.61	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.55	N;.
REVEL	Benign	0.10
Sift	Benign	0.13	T;.
Sift4G	Uncertain	0.029	D;D
Polyphen		0.0030	B;B
Vest4		0.17
MutPred		0.35		Gain of catalytic residue at S1488 (P = 0.0629);Gain of catalytic residue at S1488 (P = 0.0629);
MVP		0.38
MPC		0.29
ClinPred		0.48	T
GERP RS		3.0
Varity_R		0.18
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2080094985; hg19: chrX-73959331;