rs199960807

Variant names:

• chrX-74744424-C-T
• rs199960807
• NM_001008537.3:c.133G>A

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.133G>A​(p.Ala45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000759 in 1,205,848 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 259 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00080 (0 hom. 251 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.496
• Publications: 2 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=0.013754636).
• BP6: Variant X-74744424-C-T is Benign according to our data. Variant chrX-74744424-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289284.
• BS2: High Hemizygotes in GnomAd4 at 8 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.133G>A	p.Ala45Thr	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.133G>A	p.Ala45Thr	missense	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.133G>A	p.Ala45Thr	missense	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.133G>A	p.Ala45Thr	missense	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 35 AN: 111220 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000383

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000671

GnomAD2 exomes AF: 0.000284 AC: 50 AN: 176128 AF XY: 0.000241

Gnomad AFR exome AF: 0.0000776

Gnomad AMR exome AF: 0.0000745

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000556

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000804 AC: 880 AN: 1094574 Hom.: 0 Cov.: 30 AF XY: 0.000697 AC XY: 251 AN XY: 360152

African (AFR) AF: 0.00 AC: 0 AN: 26309

American (AMR) AF: 0.0000574 AC: 2 AN: 34831

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19231

East Asian (EAS) AF: 0.00 AC: 0 AN: 30156

South Asian (SAS) AF: 0.000298 AC: 16 AN: 53715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40377

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4081

European-Non Finnish (NFE) AF: 0.000993 AC: 834 AN: 839968

Other (OTH) AF: 0.000588 AC: 27 AN: 45906

GnomAD4 genome AF: 0.000315 AC: 35 AN: 111274 Hom.: 0 Cov.: 23 AF XY: 0.000239 AC XY: 8 AN XY: 33472

African (AFR) AF: 0.0000327 AC: 1 AN: 30622

American (AMR) AF: 0.00 AC: 0 AN: 10458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3505

South Asian (SAS) AF: 0.000384 AC: 1 AN: 2607

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000603 AC: 32 AN: 53061

Other (OTH) AF: 0.000663 AC: 1 AN: 1509

Alfa AF: 0.000424 Hom.: 17

Bravo AF: 0.000302

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000247 AC: 30

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.50
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.085
Sift	Benign	0.77	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.069
MVP		0.043
MPC		0.22
ClinPred		0.0059	T
GERP RS		1.2
Varity_R		0.043
gMVP		0.15
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: rs199960807; hg19: chrX-73964259;