rs199960807

chrX-74744424-C-T

Variant summary

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

The NM_001008537.3(NEXMIF):c.133G>A(p.Ala45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000759 in 1,205,848 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 259 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00080 (0 hom. 251 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.496

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=0.013754636).
• BP6: Variant X-74744424-C-T is Benign according to our data. Variant chrX-74744424-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289284.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=1}. Variant chrX-74744424-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.133G>A	p.Ala45Thr	missense_variant	3/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.133G>A	p.Ala45Thr	missense_variant	3/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.133G>A	p.Ala45Thr	missense_variant	3/5	1		P1
NEXMIF	ENST00000642681.2	c.133G>A	p.Ala45Thr	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 35 AN: 111220 Hom.: 0 Cov.: 23 AF XY: 0.000239 AC XY: 8 AN XY: 33408

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000383

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000671

GnomAD3 exomes AF: 0.000284 AC: 50 AN: 176128 Hom.: 0 AF XY: 0.000241 AC XY: 15 AN XY: 62152

Gnomad AFR exome AF: 0.0000776

Gnomad AMR exome AF: 0.0000745

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000556

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000804 AC: 880 AN: 1094574 Hom.: 0 Cov.: 30 AF XY: 0.000697 AC XY: 251 AN XY: 360152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000574

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000298

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000993

Gnomad4 OTH exome AF: 0.000588

GnomAD4 genome AF: 0.000315 AC: 35 AN: 111274 Hom.: 0 Cov.: 23 AF XY: 0.000239 AC XY: 8 AN XY: 33472

Gnomad4 AFR AF: 0.0000327

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000384

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000663

Alfa AF: 0.000424 Hom.: 17

Bravo AF: 0.000302

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000247 AC: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	NEXMIF: BP4, BS2 -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 09, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.92
Cadd	Benign	12
Dann	Benign	0.93
DEOGEN2	Benign	0.021	T;T;.
FATHMM_MKL	Benign	0.075	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.21	N;.;.
REVEL	Benign	0.085
Sift	Benign	0.77	T;.;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0010	B;B;.
Vest4		0.069
MVP		0.043
MPC		0.22
ClinPred		0.0059	T
GERP RS		1.2
Varity_R		0.043
gMVP		0.15

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: rs199960807; hg19: chrX-73964259;