chrX-74739448-G-A

Variant names:

• chrX-74739448-G-A
• rs973158487
• NM_001008537.3:c.4508C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001008537.3(NEXMIF):​c.4508C>T​(p.Pro1503Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000209 in 1,197,802 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 21)
  • Exomes 𝑓: 0.000021 (0 hom. 6 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.12

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.4508C>T	p.Pro1503Leu	missense_variant	Exon 4 of 4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.4508C>T	p.Pro1503Leu	missense_variant	Exon 4 of 4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.4508C>T	p.Pro1503Leu	missense_variant	Exon 4 of 5	1		ENSP00000480284.1
NEXMIF	ENST00000642681	c.*648C>T		3_prime_UTR_variant	Exon 3 of 3			ENSP00000495800.1

Frequencies

GnomAD3 genomes AF: 0.0000182 AC: 2 AN: 109860 Hom.: 0 Cov.: 21 AF XY: 0.0000622 AC XY: 2 AN XY: 32178

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000380

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000211 AC: 23 AN: 1087942 Hom.: 0 Cov.: 27 AF XY: 0.0000169 AC XY: 6 AN XY: 355324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000251

Gnomad4 OTH exome AF: 0.0000437

GnomAD4 genome AF: 0.0000182 AC: 2 AN: 109860 Hom.: 0 Cov.: 21 AF XY: 0.0000622 AC XY: 2 AN XY: 32178

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000380

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEXMIF c.4508C>T (p.Pro1503Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 1197802 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4508C>T in individuals affected with Intellectual Developmental Disorder, X-Linked 98 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2897650). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1503 of the NEXMIF protein (p.Pro1503Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	.;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.85	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.020	N;.
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.53		Loss of catalytic residue at P1503 (P = 0.1527);Loss of catalytic residue at P1503 (P = 0.1527);
MVP		0.42
MPC		0.62
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.29
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs973158487; hg19: chrX-73959283;