rs559413122

Variant names:

• chrX-74739427-C-G
• rs559413122
• NM_001008537.3:c.4529G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-74739427-C-G
• chrX-74739427-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001008537.3(NEXMIF):​c.4529G>C​(p.Arg1510Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000923 in 1,083,552 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1510H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03323978).

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.4529G>C	p.Arg1510Pro	missense	Exon 4 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.4529G>C	p.Arg1510Pro	missense	Exon 4 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.4529G>C	p.Arg1510Pro	missense	Exon 4 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.*669G>C		3_prime_UTR	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083552 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 351320

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25771

American (AMR) AF: 0.00 AC: 0 AN: 33122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19057

East Asian (EAS) AF: 0.00 AC: 0 AN: 29603

South Asian (SAS) AF: 0.00 AC: 0 AN: 51200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40331

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4068

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 834847

Other (OTH) AF: 0.00 AC: 0 AN: 45553

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.7
DANN	Benign	0.70
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.4
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.23
Sift	Benign	0.19	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.28		Gain of loop (P = 0.1069)
MVP		0.44
MPC		0.32
ClinPred		0.041	T
GERP RS		-8.2
Varity_R		0.14
gMVP		0.15
Mutation Taster		=100/0	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: rs559413122; hg19: chrX-73959262;