rs141776597

chrX-74742459-C-GchrX-74742459-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001008537.3(NEXMIF):c.2098G>C(p.Val700Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,208,489 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 199 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V700E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00052 (0 hom. 186 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.98

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013627827).
• BP6: Variant X-74742459-C-G is Benign according to our data. Variant chrX-74742459-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 435598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74742459-C-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.2098G>C	p.Val700Leu	missense_variant	3/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.2098G>C	p.Val700Leu	missense_variant	3/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.2098G>C	p.Val700Leu	missense_variant	3/5	1		P1
NEXMIF	ENST00000642681.2	c.2098G>C	p.Val700Leu	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.000411 AC: 46 AN: 111935 Hom.: 0 Cov.: 23 AF XY: 0.000381 AC XY: 13 AN XY: 34093

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000284

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000582

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000439 AC: 80 AN: 182041 Hom.: 1 AF XY: 0.000314 AC XY: 21 AN XY: 66839

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000654

Gnomad NFE exome AF: 0.000418

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000523 AC: 574 AN: 1096498 Hom.: 0 Cov.: 31 AF XY: 0.000514 AC XY: 186 AN XY: 362052

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000625

Gnomad4 ASJ exome AF: 0.00232

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.000226

Gnomad4 NFE exome AF: 0.000558

Gnomad4 OTH exome AF: 0.000478

GnomAD4 genome AF: 0.000411 AC: 46 AN: 111991 Hom.: 0 Cov.: 23 AF XY: 0.000381 AC XY: 13 AN XY: 34159

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.000284

Gnomad4 ASJ AF: 0.00189

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000165

Gnomad4 NFE AF: 0.000582

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000668 Hom.: 16

Bravo AF: 0.000434

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00104 AC: 7

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2019	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. -

NEXMIF-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.9
Dann	Benign	0.88
DEOGEN2	Benign	0.053	T;T;.
FATHMM_MKL	Benign	0.26	N
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.038
Sift	Benign	0.071	T;.;.
Sift4G	Benign	0.25	T;T;.
Polyphen		0.012	B;B;.
Vest4		0.11
MutPred		0.060		Loss of methylation at K701 (P = 0.0436);Loss of methylation at K701 (P = 0.0436);Loss of methylation at K701 (P = 0.0436);
MVP		0.12
MPC		0.23
ClinPred		0.011	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.25

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: rs141776597; hg19: chrX-73962294;