X-74740782-C-T

Variant names:

• chrX-74740782-C-T
• rs761368099
• NM_001008537.3:c.3775G>A

Variant summary

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

The NM_001008537.3(NEXMIF):​c.3775G>A​(p.Ala1259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,210,553 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 3 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.211

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=0.02157116).
• BP6: Variant X-74740782-C-T is Benign according to our data. Variant chrX-74740782-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 566213.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.3775G>A	p.Ala1259Thr	missense_variant	Exon 3 of 4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.3775G>A	p.Ala1259Thr	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.3775G>A	p.Ala1259Thr	missense_variant	Exon 3 of 5	1		ENSP00000480284.1
NEXMIF	ENST00000642681.2	c.3775G>A	p.Ala1259Thr	missense_variant	Exon 3 of 3			ENSP00000495800.1

Frequencies

GnomAD3 genomes AF: 0.000213 AC: 24 AN: 112801 Hom.: 0 Cov.: 23 AF XY: 0.000258 AC XY: 9 AN XY: 34941

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.00197

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182355 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67017

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

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: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1097752 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 3 AN XY: 363148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

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: 0.000174

GnomAD4 genome AF: 0.000213 AC: 24 AN: 112801 Hom.: 0 Cov.: 23 AF XY: 0.000258 AC XY: 9 AN XY: 34941

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00196

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: 0.00197

Bravo AF: 0.000329

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Sep 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 15, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	0.064
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.1
DANN	Benign	0.74
DEOGEN2	Benign	0.031	T;T;.
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.56	.;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.66	N;.;.
REVEL	Benign	0.072
Sift	Benign	0.41	T;.;.
Sift4G	Benign	0.30	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.061
MutPred		0.056		Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);
MVP		0.068
MPC		0.22
ClinPred		0.0095	T
GERP RS		-2.6
Varity_R		0.061
gMVP		0.46

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: rs761368099; hg19: chrX-73960617;