rs61731613

Variant names:

• chrX-74740848-T-A
• rs61731613
• NM_001008537.3:c.3709A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001008537.3(NEXMIF):​c.3709A>T​(p.Met1237Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,210,938 control chromosomes in the GnomAD database, including 3 homozygotes. There are 204 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., 104 hem., cov: 23)
  • Exomes 𝑓: 0.00037 (1 hom. 100 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.60
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062289536).
• BP6: Variant X-74740848-T-A is Benign according to our data. Variant chrX-74740848-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown,XL 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.3709A>T	p.Met1237Leu	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.3709A>T	p.Met1237Leu	missense	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.3709A>T	p.Met1237Leu	missense	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.3709A>T	p.Met1237Leu	missense	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 384 AN: 112751 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000364

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00327

GnomAD2 exomes AF: 0.000961 AC: 176 AN: 183057 AF XY: 0.000518

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000585

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: 0.000222

GnomAD4 exome AF: 0.000370 AC: 406 AN: 1098132 Hom.: 1 Cov.: 32 AF XY: 0.000275 AC XY: 100 AN XY: 363508

African (AFR) AF: 0.0124 AC: 327 AN: 26399

American (AMR) AF: 0.000483 AC: 17 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.000967 AC: 4 AN: 4136

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842084

Other (OTH) AF: 0.00124 AC: 57 AN: 46087

GnomAD4 genome AF: 0.00340 AC: 383 AN: 112806 Hom.: 2 Cov.: 23 AF XY: 0.00298 AC XY: 104 AN XY: 34958

African (AFR) AF: 0.0118 AC: 366 AN: 31117

American (AMR) AF: 0.000933 AC: 10 AN: 10717

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.000365 AC: 1 AN: 2738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6263

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53308

Other (OTH) AF: 0.00323 AC: 5 AN: 1546

Alfa AF: 0.00126 Hom.: 4

Bravo AF: 0.00405

ESP6500AA AF: 0.0128 AC: 49

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 143

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	X-linked intellectual disability, Cantagrel type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.90
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.032
Sift	Benign	0.37	T
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.28		Gain of catalytic residue at M1237 (P = 0.0035)
MVP		0.23
MPC		0.21
ClinPred		0.0097	T
GERP RS		3.8
Varity_R		0.18
gMVP		0.073
Mutation Taster		=100/0	polymorphism (auto)

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: rs61731613; hg19: chrX-73960683;