rs141776597

Variant names:

• chrX-74742459-C-G
• rs141776597
• NM_001008537.3:c.2098G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-74742459-C-G
• chrX-74742459-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001008537.3(NEXMIF):​c.2098G>C​(p.Val700Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,208,489 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 199 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V700E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00052 (0 hom. 186 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.98
• Publications: 1 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: Orphanet, Labcorp Genetics (formerly Invitae)
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013627827).
• BP6: Variant X-74742459-C-G is Benign according to our data. Variant chrX-74742459-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 13 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.2098G>C	p.Val700Leu	missense	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.2098G>C	p.Val700Leu	missense	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.2098G>C	p.Val700Leu	missense	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.2098G>C	p.Val700Leu	missense	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes AF: 0.000411 AC: 46 AN: 111935 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000284

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000582

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000439 AC: 80 AN: 182041 AF XY: 0.000314

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000654

Gnomad NFE exome AF: 0.000418

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000523 AC: 574 AN: 1096498 Hom.: 0 Cov.: 31 AF XY: 0.000514 AC XY: 186 AN XY: 362052

African (AFR) AF: 0.000114 AC: 3 AN: 26373

American (AMR) AF: 0.000625 AC: 22 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 45 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54114

European-Finnish (FIN) AF: 0.000226 AC: 9 AN: 39849

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4135

European-Non Finnish (NFE) AF: 0.000558 AC: 469 AN: 841204

Other (OTH) AF: 0.000478 AC: 22 AN: 46056

GnomAD4 genome AF: 0.000411 AC: 46 AN: 111991 Hom.: 0 Cov.: 23 AF XY: 0.000381 AC XY: 13 AN XY: 34159

African (AFR) AF: 0.000195 AC: 6 AN: 30811

American (AMR) AF: 0.000284 AC: 3 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.000165 AC: 1 AN: 6077

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000582 AC: 31 AN: 53234

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.000668 Hom.: 16

Bravo AF: 0.000434

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00104 AC: 7

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	NEXMIF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
DANN	Benign	0.88
DEOGEN2	Benign	0.053	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.038
Sift	Benign	0.071	T
Sift4G	Benign	0.25	T
Polyphen		0.012	B
Vest4		0.11
MutPred		0.060		Loss of methylation at K701 (P = 0.0436)
MVP		0.12
MPC		0.23
ClinPred		0.011	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.25
Mutation Taster		=99/1	polymorphism

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: rs141776597; hg19: chrX-73962294;