rs397518478

Positions:

• chrX-74740959-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001008537.3(NEXMIF):​c.3597_3598insA​(p.Ser1200IlefsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NEXMIF NM_001008537.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.156

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.21 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-74740959-A-AT is Pathogenic according to our data. Variant chrX-74740959-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 88753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.3597_3598insA	p.Ser1200IlefsTer5	frameshift_variant	3/4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.3597_3598insA	p.Ser1200IlefsTer5	frameshift_variant	3/4	1	NM_001008537.3	ENSP00000055682	P1
NEXMIF	ENST00000616200.2	c.3597_3598insA	p.Ser1200IlefsTer5	frameshift_variant	3/5	1		ENSP00000480284	P1
NEXMIF	ENST00000642681.2	c.3597_3598insA	p.Ser1200IlefsTer5	frameshift_variant	3/3			ENSP00000495800

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability, Cantagrel type Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2013	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.3596_3597insA; This variant is associated with the following publications: (PMID: 27812264, 33144681, 25590979, 27358180, 23615299) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with NEXMIF-related conditions (PMID: 23615299, 25590979). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 88753). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser1200Ilefs*5) in the NEXMIF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXMIF are known to be pathogenic (PMID: 23615299). -

Computational scores

Source: dbNSFP v4.3

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: rs397518478; hg19: chrX-73960794;