chrX-74743702-T-C

Variant names:

• chrX-74743702-T-C
• rs3762242
• NM_001008537.3:c.855A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001008537.3(NEXMIF):​c.855A>G​(p.Leu285Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,210,141 control chromosomes in the GnomAD database, including 23 homozygotes. There are 745 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., 69 hem., cov: 23)
  • Exomes 𝑓: 0.0018 (20 hom. 676 hem.)
• Consequence: NEXMIF NM_001008537.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.427
• Publications: 2 publications found

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]

NEXMIF Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability, Cantagrel type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-74743702-T-C is Benign according to our data. Variant chrX-74743702-T-C is described in ClinVar as Benign. ClinVar VariationId is 474076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.427 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00221 (248/112144) while in subpopulation EAS AF = 0.0312 (111/3557). AF 95% confidence interval is 0.0265. There are 3 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008537.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	NM_001008537.3	MANE Select	c.855A>G	p.Leu285Leu	synonymous	Exon 3 of 4	NP_001008537.1	Q5QGS0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	ENST00000055682.12	TSL:1 MANE Select	c.855A>G	p.Leu285Leu	synonymous	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.855A>G	p.Leu285Leu	synonymous	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.855A>G	p.Leu285Leu	synonymous	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 249 AN: 112090 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0311

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00462

GnomAD2 exomes AF: 0.00576 AC: 1054 AN: 183027 AF XY: 0.00481

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0365

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00488

GnomAD4 exome AF: 0.00184 AC: 2023 AN: 1097997 Hom.: 20 Cov.: 31 AF XY: 0.00186 AC XY: 676 AN XY: 363365

African (AFR) AF: 0.000227 AC: 6 AN: 26398

American (AMR) AF: 0.0182 AC: 640 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.0384 AC: 1160 AN: 30202

South Asian (SAS) AF: 0.00126 AC: 68 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4134

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 841920

Other (OTH) AF: 0.00289 AC: 133 AN: 46087

GnomAD4 genome AF: 0.00221 AC: 248 AN: 112144 Hom.: 3 Cov.: 23 AF XY: 0.00201 AC XY: 69 AN XY: 34314

African (AFR) AF: 0.000356 AC: 11 AN: 30919

American (AMR) AF: 0.0107 AC: 113 AN: 10542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.0312 AC: 111 AN: 3557

South Asian (SAS) AF: 0.00187 AC: 5 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6116

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53243

Other (OTH) AF: 0.00456 AC: 7 AN: 1536

Alfa AF: 0.00150 Hom.: 78

Bravo AF: 0.00343

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.62
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3762242; hg19: chrX-73963537; COSMIC: COSV107226573; COSMIC: COSV107226573;