rs41298498

Variant names:

• chrX-74741959-G-T
• rs41298498
• NM_001008537.3:c.2598C>A

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.2598C>A​(p.Ser866Ser) 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
• 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=-0.83).
• BP6: Variant X-74741959-G-T is Benign according to our data. Variant chrX-74741959-G-T is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.2598C>A	p.Ser866Ser	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.2598C>A	p.Ser866Ser	synonymous	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.2598C>A	p.Ser866Ser	synonymous	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.2598C>A	p.Ser866Ser	synonymous	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 1752 AN: 111859 Hom.: 17 Cov.: 23

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

GnomAD2 exomes AF: 0.0206 AC: 3782 AN: 183174 AF XY: 0.0226

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 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

African (AFR) AF: 0.00155 AC: 41 AN: 26394

American (AMR) AF: 0.0155 AC: 544 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 29 AN: 19384

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30202

South Asian (SAS) AF: 0.0486 AC: 2629 AN: 54140

European-Finnish (FIN) AF: 0.0423 AC: 1714 AN: 40524

Middle Eastern (MID) AF: 0.0102 AC: 42 AN: 4134

European-Non Finnish (NFE) AF: 0.0173 AC: 14604 AN: 841815

Other (OTH) AF: 0.0178 AC: 819 AN: 46082

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

African (AFR) AF: 0.00259 AC: 80 AN: 30885

American (AMR) AF: 0.0163 AC: 172 AN: 10532

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2647

East Asian (EAS) AF: 0.000564 AC: 2 AN: 3549

South Asian (SAS) AF: 0.0464 AC: 124 AN: 2672

European-Finnish (FIN) AF: 0.0410 AC: 248 AN: 6053

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.0206 AC: 1096 AN: 53157

Other (OTH) AF: 0.0125 AC: 19 AN: 1521

Alfa AF: 0.0154 Hom.: 117

Bravo AF: 0.0134

EpiCase AF: 0.0183

EpiControl AF: 0.0182

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.59
PhyloP100		-0.30
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41298498; hg19: chrX-73961794;