rs3762242

Positions:

• chrX-74743702-T-C

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.855A>G​(p.Leu285Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,210,141 control chromosomes in the GnomAD database, including 23 homozygotes. There are 745 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., 69 hem., cov: 23)
  • Exomes 𝑓: 0.0018 (20 hom. 676 hem.)
• Consequence: NEXMIF NM_001008537.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.427

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=-0.86).
• BP6: Variant X-74743702-T-C is Benign according to our data. Variant chrX-74743702-T-C is described in ClinVar as [Benign]. Clinvar id is 474076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74743702-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.427 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00221 (248/112144) while in subpopulation EAS AF= 0.0312 (111/3557). AF 95% confidence interval is 0.0265. There are 3 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.855A>G	p.Leu285Leu	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.855A>G	p.Leu285Leu	synonymous_variant	3/4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.855A>G	p.Leu285Leu	synonymous_variant	3/5	1		ENSP00000480284.1
NEXMIF	ENST00000642681.2	c.855A>G	p.Leu285Leu	synonymous_variant	3/3			ENSP00000495800.1

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 249 AN: 112090 Hom.: 3 Cov.: 23 AF XY: 0.00201 AC XY: 69 AN XY: 34250

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0311

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00462

GnomAD3 exomes AF: 0.00576 AC: 1054 AN: 183027 Hom.: 10 AF XY: 0.00481 AC XY: 325 AN XY: 67619

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0365

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00488

GnomAD4 exome AF: 0.00184 AC: 2023 AN: 1097997 Hom.: 20 Cov.: 31 AF XY: 0.00186 AC XY: 676 AN XY: 363365

Gnomad4 AFR exome AF: 0.000227

Gnomad4 AMR exome AF: 0.0182

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0384

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.00289

GnomAD4 genome AF: 0.00221 AC: 248 AN: 112144 Hom.: 3 Cov.: 23 AF XY: 0.00201 AC XY: 69 AN XY: 34314

Gnomad4 AFR AF: 0.000356

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0312

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00456

Alfa AF: 0.000907 Hom.: 34

Bravo AF: 0.00343

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs3762242; hg19: chrX-73963537;