rs41306133

Positions:

• chrX-74741756-T-C

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.2801A>G​(p.Asn934Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,209,520 control chromosomes in the GnomAD database, including 95 homozygotes. There are 5,511 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (7 hom., 360 hem., cov: 23)
  • Exomes 𝑓: 0.015 (88 hom. 5151 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.181

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=0.0036647618).
• BP6: Variant X-74741756-T-C is Benign according to our data. Variant chrX-74741756-T-C is described in ClinVar as [Benign]. Clinvar id is 474066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74741756-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0147 (16130/1097650) while in subpopulation NFE AF= 0.0165 (13860/841604). AF 95% confidence interval is 0.0162. There are 88 homozygotes in gnomad4_exome. There are 5151 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXMIF	NM_001008537.3	c.2801A>G	p.Asn934Ser	missense_variant	3/4	ENST00000055682.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXMIF	ENST00000055682.12	c.2801A>G	p.Asn934Ser	missense_variant	3/4	1	NM_001008537.3	P1
NEXMIF	ENST00000616200.2	c.2801A>G	p.Asn934Ser	missense_variant	3/5	1		P1
NEXMIF	ENST00000642681.2	c.2801A>G	p.Asn934Ser	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1169 AN: 111819 Hom.: 6 Cov.: 23 AF XY: 0.0105 AC XY: 358 AN XY: 34015

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00291

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00409

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.00470

GnomAD3 exomes AF: 0.0119 AC: 2184 AN: 183274 Hom.: 10 AF XY: 0.0120 AC XY: 812 AN XY: 67790

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.00441

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00639

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0147 AC: 16130 AN: 1097650 Hom.: 88 Cov.: 31 AF XY: 0.0142 AC XY: 5151 AN XY: 363038

Gnomad4 AFR exome AF: 0.00148

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.00562

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00617

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0165

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0105 AC: 1177 AN: 111870 Hom.: 7 Cov.: 23 AF XY: 0.0106 AC XY: 360 AN XY: 34076

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.00227

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00410

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.00464

Alfa AF: 0.0146 Hom.: 674

Bravo AF: 0.00942

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0173 AC: 50

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.0153 AC: 103

ExAC AF: 0.0117 AC: 1416

EpiCase AF: 0.0150

EpiControl AF: 0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2016

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	0.057
BayesDel_addAF	Benign	-0.91	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.016
DANN	Benign	0.15
DEOGEN2	Benign	0.019	T;T;.
FATHMM_MKL	Benign	0.36	N
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.67	N;.;.
REVEL	Benign	0.10
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.035
MPC		0.18
ClinPred		0.0027	T
GERP RS		-7.2
Varity_R		0.033
gMVP		0.058

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: rs41306133; hg19: chrX-73961591;