rs186535459

chrX-74741885-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001008537.3(NEXMIF):c.2672A>G(p.Asn891Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000859 in 1,210,456 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N891N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000086 (0 hom. 23 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0400

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008425474).
• BP6: Variant X-74741885-T-C is Benign according to our data. Variant chrX-74741885-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93464.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}.
• BS2: High Hemizygotes in GnomAdExome at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.2672A>G	p.Asn891Ser	missense_variant	3/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.2672A>G	p.Asn891Ser	missense_variant	3/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.2672A>G	p.Asn891Ser	missense_variant	3/5	1		P1
NEXMIF	ENST00000642681.2	c.2672A>G	p.Asn891Ser	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0000801 AC: 9 AN: 112335 Hom.: 0 Cov.: 22 AF XY: 0.0000290 AC XY: 1 AN XY: 34505

Gnomad AFR AF: 0.0000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000660

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000448 AC: 82 AN: 183202 Hom.: 0 AF XY: 0.000251 AC XY: 17 AN XY: 67714

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000856 AC: 94 AN: 1098065 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 23 AN XY: 363435

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000890 AC: 10 AN: 112391 Hom.: 0 Cov.: 22 AF XY: 0.0000289 AC XY: 1 AN XY: 34571

Gnomad4 AFR AF: 0.0000968

Gnomad4 AMR AF: 0.000660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.000354 AC: 43

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2017

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

Jan 18, 2024

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	0.067
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-1.0
Cadd	Benign	11
Dann	Benign	0.95
DEOGEN2	Benign	0.017	T;T;.
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.43	N;.;.
REVEL	Benign	0.12
Sift	Benign	0.25	T;.;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0020	B;B;.
Vest4		0.029
MVP		0.15
MPC		0.18
ClinPred		0.025	T
GERP RS		1.3
Varity_R		0.037
gMVP		0.047

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: rs186535459; hg19: chrX-73961720;