rs375623451

Positions:

• chrX-74741606-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.2951A>G​(p.Asn984Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,097,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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: not found (cov: 22)
  • Exomes 𝑓: 0.000033 (0 hom. 7 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0710

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=0.021386862).
• BP6: Variant X-74741606-T-C is Benign according to our data. Variant chrX-74741606-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474067.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.2951A>G	p.Asn984Ser	missense_variant	3/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.2951A>G	p.Asn984Ser	missense_variant	3/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.2951A>G	p.Asn984Ser	missense_variant	3/5	1		P1
NEXMIF	ENST00000642681.2	c.2951A>G	p.Asn984Ser	missense_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.000126 AC: 23 AN: 183160 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67702

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000803

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 36 AN: 1097965 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 7 AN XY: 363335

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000739

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: 0.0000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

History of neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2017

There is insufficient or conflicting evidence for classification of this alteration. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.061
DANN	Benign	0.19
DEOGEN2	Benign	0.020	T;T;.
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.12	N;.;.
REVEL	Benign	0.039
Sift	Benign	1.0	T;.;.
Sift4G	Benign	0.73	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.034
MVP		0.068
MPC		0.18
ClinPred		0.011	T
GERP RS		-2.1
Varity_R		0.029
gMVP		0.051

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: rs375623451; hg19: chrX-73961441;