rs41298498

Positions:

• chrX-74741959-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001008537.3(NEXMIF):​c.2598C>A​(p.Ser866=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 1,209,789 control chromosomes in the GnomAD database, including 167 homozygotes. There are 7,772 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (17 hom., 565 hem., cov: 23)
  • Exomes 𝑓: 0.019 (150 hom. 7207 hem.)
• Consequence: NEXMIF NM_001008537.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.305

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-74741959-G-T is Benign according to our data. Variant chrX-74741959-G-T is described in ClinVar as [Benign]. Clinvar id is 129383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.305 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0157 (1752/111916) while in subpopulation SAS AF= 0.0464 (124/2672). AF 95% confidence interval is 0.0398. There are 17 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.2598C>A	p.Ser866=	synonymous_variant	3/4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.2598C>A	p.Ser866=	synonymous_variant	3/4	1	NM_001008537.3	ENSP00000055682	P1
NEXMIF	ENST00000616200.2	c.2598C>A	p.Ser866=	synonymous_variant	3/5	1		ENSP00000480284	P1
NEXMIF	ENST00000642681.2	c.2598C>A	p.Ser866=	synonymous_variant	3/3			ENSP00000495800

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 1752 AN: 111859 Hom.: 17 Cov.: 23 AF XY: 0.0166 AC XY: 564 AN XY: 34017

Gnomad AFR AF: 0.00260

Gnomad AMI AF: 0.00732

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.000562

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.0410

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0126

GnomAD3 exomes AF: 0.0206 AC: 3782 AN: 183174 Hom.: 36 AF XY: 0.0226 AC XY: 1533 AN XY: 67716

Gnomad AFR exome AF: 0.00205

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.000936

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0491

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0186 AC: 20424 AN: 1097873 Hom.: 150 Cov.: 32 AF XY: 0.0198 AC XY: 7207 AN XY: 363249

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.0155

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.0486

Gnomad4 FIN exome AF: 0.0423

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0157 AC: 1752 AN: 111916 Hom.: 17 Cov.: 23 AF XY: 0.0166 AC XY: 565 AN XY: 34084

Gnomad4 AFR AF: 0.00259

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00189

Gnomad4 EAS AF: 0.000564

Gnomad4 SAS AF: 0.0464

Gnomad4 FIN AF: 0.0410

Gnomad4 NFE AF: 0.0206

Gnomad4 OTH AF: 0.0125

Alfa AF: 0.0154 Hom.: 117

Bravo AF: 0.0134

EpiCase AF: 0.0183

EpiControl AF: 0.0182

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41298498; hg19: chrX-73961794;