X-74742553-ATCT-A

Variant names:

• chrX-74742553-ATCT-A
• rs764439412
• NM_001008537.3:c.2001_2003delAGA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_001008537.3(NEXMIF):​c.2001_2003delAGA​(p.Glu667del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,207,812 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000032 (0 hom. 12 hem.)
• Consequence: NEXMIF NM_001008537.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.67
• 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: Likely_benign. The variant received -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001008537.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-74742553-ATCT-A is Benign according to our data. Variant chrX-74742553-ATCT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211261.
• BS2: High Hemizygotes in GnomAd4 at 3 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.2001_2003delAGA	p.Glu667del	disruptive_inframe_deletion	Exon 3 of 4	NP_001008537.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	ENST00000055682.12	TSL:1 MANE Select	c.2001_2003delAGA	p.Glu667del	disruptive_inframe_deletion	Exon 3 of 4	ENSP00000055682.5
	NEXMIF	ENST00000616200.2	TSL:1	c.2001_2003delAGA	p.Glu667del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000480284.1
	NEXMIF	ENST00000642681.2		c.2001_2003delAGA	p.Glu667del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000495800.1

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111785 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

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: 0.0000564

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000339 AC: 6 AN: 176806 AF XY: 0.0000321

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000385

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000319 AC: 35 AN: 1096027 Hom.: 0 AF XY: 0.0000332 AC XY: 12 AN XY: 361675

African (AFR) AF: 0.00 AC: 0 AN: 26373

American (AMR) AF: 0.000257 AC: 9 AN: 35060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19346

East Asian (EAS) AF: 0.00 AC: 0 AN: 30160

South Asian (SAS) AF: 0.00 AC: 0 AN: 53952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000250 AC: 21 AN: 841088

Other (OTH) AF: 0.000109 AC: 5 AN: 46010

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111785 Hom.: 0 Cov.: 22 AF XY: 0.0000883 AC XY: 3 AN XY: 33971

African (AFR) AF: 0.00 AC: 0 AN: 30702

American (AMR) AF: 0.0000950 AC: 1 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3544

South Asian (SAS) AF: 0.00 AC: 0 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53171

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=71/29	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: rs764439412; hg19: chrX-73962388;