chr9-137449938-G-T

Position:

• chr9-137449938-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001130969.3(NSMF):​c.1404C>A​(p.Asn468Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSMF NM_001130969.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSMF	NM_001130969.3	c.1404C>A	p.Asn468Lys	missense_variant	14/16	ENST00000371475.9	NP_001124441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSMF	ENST00000371475.9	c.1404C>A	p.Asn468Lys	missense_variant	14/16	1	NM_001130969.3	ENSP00000360530	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2017

The N466K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). N466K is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	.;.;.;.;D;.
Eigen	Benign	0.032
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	.;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Benign	0.098
Sift	Uncertain	0.0090	D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.82	P;.;P;P;P;P
Vest4		0.81
MutPred		0.36		.;.;.;.;Gain of methylation at N468 (P = 0.0062);.;
MVP		0.45
MPC		1.5
ClinPred		0.96	D
GERP RS		1.7
Varity_R		0.36
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs748795896; hg19: chr9-140344390; COSMIC: COSV55810494; COSMIC: COSV55810494;