rs1556016438

Positions:

• chrX-74741883-TG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001008537.3(NEXMIF):​c.2673del​(p.Asn891LysfsTer18) variant causes a frameshift change. 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, single submitter P:1
• Conservation: PhyloP100: 4.46

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_pathogenic. Variant got 8 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 0.413 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-74741883-TG-T is Pathogenic according to our data. Variant chrX-74741883-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 474064.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.2673del	p.Asn891LysfsTer18	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.2673del	p.Asn891LysfsTer18	frameshift_variant	3/4	1	NM_001008537.3	ENSP00000055682	P1
NEXMIF	ENST00000616200.2	c.2673del	p.Asn891LysfsTer18	frameshift_variant	3/5	1		ENSP00000480284	P1
NEXMIF	ENST00000642681.2	c.2673del	p.Asn891LysfsTer18	frameshift_variant	3/3			ENSP00000495800

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 17, 2017

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in KIAA2022 are known to be pathogenic (PMID: 23615299). This sequence change deletes 1 nucleotide from exon 3 of the KIAA2022 mRNA (c.2673delC), causing a frameshift at codon 891. This creates a premature translational stop signal (p.Asn891Lysfs*18) and is expected to result in an absent or disrupted protein product. -

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: rs1556016438; hg19: chrX-73961718;