rs149185175

Variant names:

• chrX-74740759-G-A
• rs149185175
• NM_001008537.3:c.3798C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001008537.3(NEXMIF):​c.3798C>T​(p.Gly1266Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,210,710 control chromosomes in the GnomAD database, including 8 homozygotes. There are 297 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., 139 hem., cov: 23)
  • Exomes 𝑓: 0.00056 (4 hom. 158 hem.)
• Consequence: NEXMIF NM_001008537.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.343
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-74740759-G-A is Benign according to our data. Variant chrX-74740759-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.343 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00479 (540/112808) while in subpopulation AFR AF = 0.0166 (516/31143). AF 95% confidence interval is 0.0154. There are 4 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.3798C>T	p.Gly1266Gly	synonymous	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.3798C>T	p.Gly1266Gly	synonymous	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.3798C>T	p.Gly1266Gly	synonymous	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.3798C>T	p.Gly1266Gly	synonymous	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 539 AN: 112757 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000563

Gnomad OTH AF: 0.00459

GnomAD2 exomes AF: 0.00140 AC: 256 AN: 182511 AF XY: 0.000834

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00102

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: 0.00155

GnomAD4 exome AF: 0.000559 AC: 614 AN: 1097902 Hom.: 4 Cov.: 32 AF XY: 0.000435 AC XY: 158 AN XY: 363304

African (AFR) AF: 0.0199 AC: 524 AN: 26394

American (AMR) AF: 0.00119 AC: 42 AN: 35171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 54107

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40502

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

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 841939

Other (OTH) AF: 0.000846 AC: 39 AN: 46081

GnomAD4 genome AF: 0.00479 AC: 540 AN: 112808 Hom.: 4 Cov.: 23 AF XY: 0.00398 AC XY: 139 AN XY: 34962

African (AFR) AF: 0.0166 AC: 516 AN: 31143

American (AMR) AF: 0.00131 AC: 14 AN: 10698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2743

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6240

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

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53319

Other (OTH) AF: 0.00453 AC: 7 AN: 1544

Alfa AF: 0.00386 Hom.: 15

Bravo AF: 0.00583

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.46
DANN	Benign	0.39
PhyloP100		0.34
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: rs149185175; hg19: chrX-73960594;