X-74739463-G-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.4493C>T(p.Thr1498Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 109,722 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1498N) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 21)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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=0.09232098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.4493C>T	p.Thr1498Ile	missense_variant	4/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.4493C>T	p.Thr1498Ile	missense_variant	4/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.4493C>T	p.Thr1498Ile	missense_variant	4/5	1		P1
NEXMIF	ENST00000642681.2	c.*633C>T		3_prime_UTR_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0000182 AC: 2 AN: 109722 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32016

Gnomad AFR AF: 0.0000664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome AF: 0.0000182 AC: 2 AN: 109722 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32016

Gnomad4 AFR AF: 0.0000664

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

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

Oct 27, 2022

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 648767). This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1498 of the NEXMIF protein (p.Thr1498Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.045	T;T
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.0	N;.
REVEL	Benign	0.074
Sift	Uncertain	0.011	D;.
Sift4G	Benign	0.094	T;T
Polyphen		0.069	B;B
Vest4		0.20
MutPred		0.32		Loss of ubiquitination at K1494 (P = 0.0653);Loss of ubiquitination at K1494 (P = 0.0653);
MVP		0.10
MPC		0.30
ClinPred		0.54	D
GERP RS		4.5
Varity_R		0.16
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs145525836; hg19: chrX-73959298;