rs186535459

Variant names:

• chrX-74741885-T-C
• rs186535459
• NM_001008537.3:c.2672A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001008537.3(NEXMIF):​c.2672A>G​(p.Asn891Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000859 in 1,210,456 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N891N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000086 (0 hom. 23 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.0400
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008425474).
• BP6: Variant X-74741885-T-C is Benign according to our data. Variant chrX-74741885-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93464.
• BS2: High Hemizygotes in GnomAdExome4 at 23 XL,Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	NM_001008537.3	MANE Select	c.2672A>G	p.Asn891Ser	missense	Exon 3 of 4	NP_001008537.1	Q5QGS0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	ENST00000055682.12	TSL:1 MANE Select	c.2672A>G	p.Asn891Ser	missense	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.2672A>G	p.Asn891Ser	missense	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.2672A>G	p.Asn891Ser	missense	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes AF: 0.0000801 AC: 9 AN: 112335 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000448 AC: 82 AN: 183202 AF XY: 0.000251

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000856 AC: 94 AN: 1098065 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 23 AN XY: 363435

African (AFR) AF: 0.000114 AC: 3 AN: 26397

American (AMR) AF: 0.00259 AC: 91 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841994

Other (OTH) AF: 0.00 AC: 0 AN: 46090

GnomAD4 genome AF: 0.0000890 AC: 10 AN: 112391 Hom.: 0 Cov.: 22 AF XY: 0.0000289 AC XY: 1 AN XY: 34571

African (AFR) AF: 0.0000968 AC: 3 AN: 30989

American (AMR) AF: 0.000660 AC: 7 AN: 10612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53243

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.000354 AC: 43

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	NEXMIF-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.040
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.12
Sift	Benign	0.25	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.029
MVP		0.15
MPC		0.18
ClinPred		0.025	T
GERP RS		1.3
Varity_R		0.037
gMVP		0.047
Mutation Taster		=100/0	polymorphism

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: rs186535459; hg19: chrX-73961720;