rs762464608

chrX-74742316-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001008537.3(NEXMIF):c.2241C>A(p.Ser747Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,097,576 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes 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 (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 6 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.465

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11951938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.2241C>A	p.Ser747Arg	missense_variant	3/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.2241C>A	p.Ser747Arg	missense_variant	3/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.2241C>A	p.Ser747Arg	missense_variant	3/5	1		P1
NEXMIF	ENST00000642681.2	c.2241C>A	p.Ser747Arg	missense_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000273 AC: 5 AN: 183000 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

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: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1097576 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 6 AN XY: 362952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

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: 0.0000154

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 541119). This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. This variant is present in population databases (rs762464608, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 747 of the NEXMIF protein (p.Ser747Arg). -

X-linked intellectual disability, Cantagrel type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.052	T;T;.
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.52	N;.;.
REVEL	Benign	0.015
Sift	Uncertain	0.010	D;.;.
Sift4G	Uncertain	0.017	D;D;.
Polyphen		0.14	B;B;.
Vest4		0.23
MutPred		0.14		Gain of MoRF binding (P = 0.0329);Gain of MoRF binding (P = 0.0329);Gain of MoRF binding (P = 0.0329);
MVP		0.18
MPC		0.29
ClinPred		0.12	T
GERP RS		3.6
Varity_R		0.23
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs762464608; hg19: chrX-73962151;