chr9-137449500-A-G

Variant names:

• chr9-137449500-A-G
• rs200465164
• NM_001130969.3:c.1496-9T>C

Variant summary

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

The NM_001130969.3(NSMF):​c.1496-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,612,620 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: NSMF NM_001130969.3 intron
• Scores: Splicing: ADA: 0.0007473
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00600
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 9-137449500-A-G is Benign according to our data. Variant chr9-137449500-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 781936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 156 AD gene.

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.1496-9T>C		intron	N/A	NP_001124441.1	Q6X4W1-1
	NSMF	NM_015537.5		c.1490-9T>C		intron	N/A	NP_056352.3
	NSMF	NM_001130970.2		c.1427-9T>C		intron	N/A	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.1496-9T>C		intron	N/A	ENSP00000360530.3	Q6X4W1-1
	NSMF	ENST00000265663.12	TSL:1	c.1490-9T>C		intron	N/A	ENSP00000265663.7	Q6X4W1-2
	NSMF	ENST00000371472.6	TSL:2	c.1490-9T>C		intron	N/A	ENSP00000360527.1	Q6X4W1-2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00107 AC: 268 AN: 249854 AF XY: 0.00107

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00147 AC: 2146 AN: 1460388 Hom.: 3 Cov.: 31 AF XY: 0.00143 AC XY: 1040 AN XY: 726478

African (AFR) AF: 0.000179 AC: 6 AN: 33474

American (AMR) AF: 0.000470 AC: 21 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 299 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.000555 AC: 29 AN: 52206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00148 AC: 1647 AN: 1111796

Other (OTH) AF: 0.00237 AC: 143 AN: 60366

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000940 AC XY: 70 AN XY: 74432

African (AFR) AF: 0.000169 AC: 7 AN: 41530

American (AMR) AF: 0.00216 AC: 33 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00168 Hom.: 1

Bravo AF: 0.00122

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.3
DANN	Benign	0.72
PhyloP100		0.0060
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00075
dbscSNV1_RF	Benign	0.026
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: rs200465164; hg19: chr9-140343952;