X-74741648-T-A

Variant names:

• chrX-74741648-T-A
• rs1556016404
• NM_001008537.3:c.2909A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001008537.3(NEXMIF):​c.2909A>T​(p.Asn970Ile) variant causes a missense 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. 12/20 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. N970S) has been classified 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: 0.945
• Publications: 0 publications found

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]

NEXMIF Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability, Cantagrel type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26768532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.2909A>T	p.Asn970Ile	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.2909A>T	p.Asn970Ile	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.2909A>T	p.Asn970Ile	missense_variant	Exon 3 of 5	1		ENSP00000480284.1
NEXMIF	ENST00000642681.2	c.2909A>T	p.Asn970Ile	missense_variant	Exon 3 of 3			ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 16, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	.;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.94
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.7	D;.;.
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.040	D;D;.
Polyphen		0.77	P;P;.
Vest4		0.68
MutPred		0.59		Loss of disorder (P = 0.0701);Loss of disorder (P = 0.0701);Loss of disorder (P = 0.0701);
MVP		0.12
MPC		0.53
ClinPred		0.95	D
GERP RS		0.27
Varity_R		0.35
gMVP		0.26
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1556016404; hg19: chrX-73961483;