X-74739491-C-T

Position:

• chrX-74739491-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001008537.3(NEXMIF):​c.4465G>A​(p.Asp1489Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,074,334 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 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)
  • Exomes 𝑓: 0.0000056 (0 hom. 2 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.128

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03272724).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.4465G>A	p.Asp1489Asn	missense_variant	4/4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.4465G>A	p.Asp1489Asn	missense_variant	4/4	1	NM_001008537.3	ENSP00000055682	P1
NEXMIF	ENST00000616200.2	c.4465G>A	p.Asp1489Asn	missense_variant	4/5	1		ENSP00000480284	P1
NEXMIF	ENST00000642681.2	c.*605G>A		3_prime_UTR_variant	3/3			ENSP00000495800

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.0000121 AC: 2 AN: 165637 Hom.: 0 AF XY: 0.0000189 AC XY: 1 AN XY: 52933

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000558 AC: 6 AN: 1074334 Hom.: 0 Cov.: 25 AF XY: 0.00000585 AC XY: 2 AN XY: 341816

Gnomad4 AFR exome AF: 0.0000776

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000485

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 08, 2023	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1313198). This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1489 of the NEXMIF protein (p.Asp1489Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.92
DEOGEN2	Benign	0.057	T;T
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.24	N;.
REVEL	Benign	0.019
Sift	Benign	0.23	T;.
Sift4G	Benign	0.65	T;T
Polyphen		0.013	B;B
Vest4		0.14
MutPred		0.23		Loss of stability (P = 0.0951);Loss of stability (P = 0.0951);
MVP		0.16
MPC		0.22
ClinPred		0.035	T
GERP RS		0.63
Varity_R		0.058
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs751841142; hg19: chrX-73959326;