rs886041701

Positions:

• chrX-74743116-G-A
• chrX-74743116-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001008537.3(NEXMIF):​c.1441C>T​(p.Arg481Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R481R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NEXMIF NM_001008537.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.03

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 18 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 61 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-74743116-G-A is Pathogenic according to our data. Variant chrX-74743116-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.1441C>T	p.Arg481Ter	stop_gained	3/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.1441C>T	p.Arg481Ter	stop_gained	3/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.1441C>T	p.Arg481Ter	stop_gained	3/5	1		P1
NEXMIF	ENST00000642681.2	c.1441C>T	p.Arg481Ter	stop_gained	3/3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1097739 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363137

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability, Cantagrel type Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 09, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Jan 18, 2024	The NEXMIF c.1441C>T (p.Arg481Ter) variant has been reported to occur de novo in at least one individual and has been described in at least three families with intellectual disability, with both affected males and females described (de Lange IM et al., PMID: 27358180; Stamberger H et al., PMID: 33144681; Webster R et al., PMID: 27568816; Brea-Fern√°ndez AJ et al., PMID: 35322241). This variant has been reported in the ClinVar database as a germline pathogenic variant by nine submitters and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 11, 2022	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2_MOD, PS4_MOD, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2023	Nonsense 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27568816, 27358180, 33144681, 31175295, 35032046) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	This sequence change creates a premature translational stop signal (p.Arg481*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of NEXMIF-related conditions (PMID: 27358180). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280509). For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2020

The c.1441C>T (p.R481*) alteration, located in exon 3 (coding exon 2) of the KIAA2022 gene, consists of a C to T substitution at nucleotide position 1441. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 481. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. In one study, this mutation was detected in a nonverbal, nonambulatory female who also had intellectual disability, microcephaly, dysmorphic features, and hypotonia (de Lange, 2016). In our internal cohort, this variant occurred de novo in two females; one individual presented with epilepsy while the other presented with hypotonia, developmental delay, and dysmorphic features (Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
Vest4		0.41
GERP RS		2.9

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: rs886041701; hg19: chrX-73962951; COSMIC: COSV50111243; COSMIC: COSV50111243;