rs121918340

Variant names:

• chr9-137449656-T-C
• rs121918340
• NM_001130969.3:c.1438A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130969.3(NSMF):​c.1438A>G​(p.Thr480Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NSMF NM_001130969.3 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 2.77
• Publications: 8 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19740829).

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.1438A>G	p.Thr480Ala	missense	Exon 15 of 16	NP_001124441.1	Q6X4W1-1
	NSMF	NM_015537.5		c.1432A>G	p.Thr478Ala	missense	Exon 14 of 15	NP_056352.3
	NSMF	NM_001130970.2		c.1369A>G	p.Thr457Ala	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.1438A>G	p.Thr480Ala	missense	Exon 15 of 16	ENSP00000360530.3	Q6X4W1-1
	NSMF	ENST00000265663.12	TSL:1	c.1432A>G	p.Thr478Ala	missense	Exon 14 of 15	ENSP00000265663.7	Q6X4W1-2
	NSMF	ENST00000371472.6	TSL:2	c.1432A>G	p.Thr478Ala	missense	Exon 14 of 16	ENSP00000360527.1	Q6X4W1-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: risk factor

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.034
Sift	Benign	0.29	T
Sift4G	Benign	0.13	T
Polyphen		0.20	B
Vest4		0.34
MutPred		0.18		Gain of helix (P = 0.0854)
MVP		0.21
MPC		0.65
ClinPred		0.30	T
GERP RS		2.5
Varity_R		0.068
gMVP		0.55
Mutation Taster		=0/100	disease causing

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: rs121918340; hg19: chr9-140344108;