chrX-74740904-T-C

Variant names:

• chrX-74740904-T-C
• rs946717276
• NM_001008537.3:c.3653A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001008537.3(NEXMIF):​c.3653A>G​(p.Gln1218Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29435652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.3653A>G	p.Gln1218Arg	missense_variant	Exon 3 of 4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.3653A>G	p.Gln1218Arg	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.3653A>G	p.Gln1218Arg	missense_variant	Exon 3 of 5	1		ENSP00000480284.1
NEXMIF	ENST00000642681.2	c.3653A>G	p.Gln1218Arg	missense_variant	Exon 3 of 3			ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with KIAA2022-related disease. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with arginine at codon 1218 of the KIAA2022 protein (p.Gln1218Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N;.;.
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.044	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.58
MutPred		0.095		Gain of catalytic residue at Q1218 (P = 0.0305);Gain of catalytic residue at Q1218 (P = 0.0305);Gain of catalytic residue at Q1218 (P = 0.0305);
MVP		0.43
MPC		0.87
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.57
gMVP		0.67

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: rs946717276; hg19: chrX-73960739;