NM_001008537.3:c.3230delC

Variant names:

• chrX-74741326-AG-A
• rs1556016350
• NM_001008537.3:c.3230delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001008537.3(NEXMIF):​c.3230delC​(p.Pro1077LeufsTer13) variant causes a frameshift 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: NEXMIF NM_001008537.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-74741326-AG-A is Pathogenic according to our data. Variant chrX-74741326-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 541125.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008537.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	NM_001008537.3	MANE Select	c.3230delC	p.Pro1077LeufsTer13	frameshift	Exon 3 of 4	NP_001008537.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	ENST00000055682.12	TSL:1 MANE Select	c.3230delC	p.Pro1077LeufsTer13	frameshift	Exon 3 of 4	ENSP00000055682.5
	NEXMIF	ENST00000616200.2	TSL:1	c.3230delC	p.Pro1077LeufsTer13	frameshift	Exon 3 of 5	ENSP00000480284.1
	NEXMIF	ENST00000642681.2		c.3230delC	p.Pro1077LeufsTer13	frameshift	Exon 3 of 3	ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 10, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro1077Leufs*13) in the KIAA2022 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with KIAA2022-related conditions. ClinVar contains an entry for this variant (Variation ID: 541125). Loss-of-function variants in KIAA2022 are known to be pathogenic (PMID: 23615299). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1556016350; hg19: chrX-73961161;