rs1556016529

Variant names:

• chrX-74742389-TTA-GT
• rs1556016529
• NM_001008537.3:c.2166_2168delTAAinsAC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001008537.3(NEXMIF):​c.2166_2168delTAAinsAC​(p.Phe722LeufsTer7) variant causes a frameshift, missense change involving the alteration of a 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: 22)
• Consequence: NEXMIF NM_001008537.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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 12 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. There are 51 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-74742389-TTA-GT is Pathogenic according to our data. Variant chrX-74742389-TTA-GT is described in ClinVar as [Pathogenic]. Clinvar id is 474060.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.2166_2168delTAAinsAC	p.Phe722LeufsTer7	frameshift_variant, 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.2166_2168delTAAinsAC	p.Phe722LeufsTer7	frameshift_variant, missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.2166_2168delTAAinsAC	p.Phe722LeufsTer7	frameshift_variant, missense_variant	Exon 3 of 5	1		ENSP00000480284.1
NEXMIF	ENST00000642681.2	c.2166_2168delTAAinsAC	p.Phe722LeufsTer7	frameshift_variant, missense_variant	Exon 3 of 3			ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability, Cantagrel type Pathogenic:1

Apr 27, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 3 nucleotides and inserts 2 nucleotides in exon 3 of the KIAA2022 mRNA (c.2166_2168delinsAC), causing a frameshift at codon 722. This creates a premature translational stop signal (p.Phe722Leufs*7) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in KIAA2022 are known to be pathogenic (PMID: 27358180, 23615299). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556016529; hg19: chrX-73962224;