rs1556016358

Positions:

• chrX-74741355-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001008537.3(NEXMIF):​c.3202C>T​(p.Leu1068Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,159 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.42

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.3202C>T	p.Leu1068Phe	missense_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.3202C>T	p.Leu1068Phe	missense_variant	3/4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.3202C>T	p.Leu1068Phe	missense_variant	3/5	1		ENSP00000480284.1
NEXMIF	ENST00000642681.2	c.3202C>T	p.Leu1068Phe	missense_variant	3/3			ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098159 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363529

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: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

X-linked intellectual disability, Cantagrel type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.53	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D;.;.
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.035	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.64
MutPred		0.076		Gain of glycosylation at S1069 (P = 0.075);Gain of glycosylation at S1069 (P = 0.075);Gain of glycosylation at S1069 (P = 0.075);
MVP		0.70
MPC		0.85
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.40

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: rs1556016358; hg19: chrX-73961190; COSMIC: COSV104545414; COSMIC: COSV104545414;