NM_001130969.3:c.1435A>G

Variant names:

• chr9-137449659-T-C
• rs1174502792
• NM_001130969.3:c.1435A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001130969.3(NSMF):​c.1435A>G​(p.Arg479Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,612,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NSMF NM_001130969.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52
• Publications: 0 publications found

Genes affected

NSMF (HGNC:29843): (NMDA receptor synaptonuclear signaling and neuronal migration factor) The protein encoded by this gene is involved in guidance of olfactory axon projections and migration of luteinizing hormone-releasing hormone neurons. Defects in this gene are a cause of idiopathic hypogonadotropic hypogonadism (IHH). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

NSMF Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 9 with or without anosmia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36682212).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130969.3. 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
	NSMF	NM_001130969.3	MANE Select	c.1435A>G	p.Arg479Gly	missense	Exon 15 of 16	NP_001124441.1	Q6X4W1-1
	NSMF	NM_015537.5		c.1429A>G	p.Arg477Gly	missense	Exon 14 of 15	NP_056352.3
	NSMF	NM_001130970.2		c.1366A>G	p.Arg456Gly	missense	Exon 14 of 15	NP_001124442.1	Q6X4W1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMF	ENST00000371475.9	TSL:1 MANE Select	c.1435A>G	p.Arg479Gly	missense	Exon 15 of 16	ENSP00000360530.3	Q6X4W1-1
	NSMF	ENST00000265663.12	TSL:1	c.1429A>G	p.Arg477Gly	missense	Exon 14 of 15	ENSP00000265663.7	Q6X4W1-2
	NSMF	ENST00000371472.6	TSL:2	c.1429A>G	p.Arg477Gly	missense	Exon 14 of 16	ENSP00000360527.1	Q6X4W1-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247932 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460300 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726348

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111654

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypogonadotropic hypogonadism 9 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.80	P
Vest4		0.56
MutPred		0.40		Loss of helix (P = 0.0104)
MVP		0.36
MPC		1.1
ClinPred		0.87	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.74
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1174502792; hg19: chr9-140344111;