rs145018752

chrX-74744406-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001008537.3(NEXMIF):c.151C>A(p.Pro51Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,207,568 control chromosomes in the GnomAD database, including 16 homozygotes. There are 389 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 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. P51L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., 187 hem., cov: 23)
  • Exomes 𝑓: 0.00069 (6 hom. 202 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.730

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003943175).
• BP6: Variant X-74744406-G-T is Benign according to our data. Variant chrX-74744406-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 129382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00664 (739/111323) while in subpopulation AFR AF= 0.0228 (699/30633). AF 95% confidence interval is 0.0214. There are 10 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.151C>A	p.Pro51Thr	missense_variant	3/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.151C>A	p.Pro51Thr	missense_variant	3/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.151C>A	p.Pro51Thr	missense_variant	3/5	1		P1
NEXMIF	ENST00000642681.2	c.151C>A	p.Pro51Thr	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 737 AN: 111270 Hom.: 10 Cov.: 23 AF XY: 0.00553 AC XY: 185 AN XY: 33482

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

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: 0.00805

GnomAD3 exomes AF: 0.00194 AC: 347 AN: 178482 Hom.: 6 AF XY: 0.00109 AC XY: 70 AN XY: 64152

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000538

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000689 AC: 755 AN: 1096245 Hom.: 6 Cov.: 31 AF XY: 0.000558 AC XY: 202 AN XY: 361731

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.000996

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000357

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00664 AC: 739 AN: 111323 Hom.: 10 Cov.: 23 AF XY: 0.00557 AC XY: 187 AN XY: 33545

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.00268

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: 0.00795

Alfa AF: 0.000782 Hom.: 28

Bravo AF: 0.00742

ESP6500AA AF: 0.0282 AC: 108

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00213 AC: 259

ClinVar

Significance: Benign/Likely 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	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 02, 2017	- -

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
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-1.0
Cadd	Benign	2.0
Dann	Benign	0.72
DEOGEN2	Benign	0.020	T;T;.
FATHMM_MKL	Benign	0.29	N
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.62	N;.;.
REVEL	Benign	0.013
Sift	Benign	0.29	T;.;.
Sift4G	Benign	0.69	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.043
MVP		0.043
MPC		0.25
ClinPred		0.0014	T
GERP RS		1.9
Varity_R		0.051
gMVP		0.18

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: rs145018752; hg19: chrX-73964241;