rs1555659856

Variant names:

• chr17-77402335-AG-CC
• rs1555659856
• NM_001113491.2:c.353_354delAGinsCC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001113491.2(SEPTIN9):​c.353_354delAGinsCC​(p.Gln118Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000293 in 81 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q118H) has been classified as Uncertain significance.

• Frequency: GnomAD MNV: 𝑓 0.00029 Genomes: not found (cov: 32)
• Consequence: SEPTIN9 NM_001113491.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 5.69
• Publications: 0 publications found

Genes affected

SEPTIN9 (HGNC:7323): (septin 9) This gene is a member of the septin family involved in cytokinesis and cell cycle control. This gene is a candidate for the ovarian tumor suppressor gene. Mutations in this gene cause hereditary neuralgic amyotrophy, also known as neuritis with brachial predilection. A chromosomal translocation involving this gene on chromosome 17 and the MLL gene on chromosome 11 results in acute myelomonocytic leukemia. Multiple alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Mar 2009]

SEPTIN9 Gene-Disease associations (from GenCC):

• amyotrophic neuralgia

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• neuralgic amyotrophy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 17-77402335-AG-CC is Benign according to our data. Variant chr17-77402335-AG-CC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446761.
• BS2: High AC in GnomAdMnv at 81 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113491.2. 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
	SEPTIN9	NM_001113491.2	MANE Select	c.353_354delAGinsCC	p.Gln118Pro	missense	N/A	NP_001106963.1	Q9UHD8-1
	SEPTIN9	NM_006640.5	MANE Plus Clinical	c.299_300delAGinsCC	p.Gln100Pro	missense	N/A	NP_006631.2	Q9UHD8-2
	SEPTIN9	NM_001113493.2		c.332_333delAGinsCC	p.Gln111Pro	missense	N/A	NP_001106965.1	Q9UHD8-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN9	ENST00000427177.6	TSL:1 MANE Select	c.353_354delAGinsCC	p.Gln118Pro	missense	N/A	ENSP00000391249.1	Q9UHD8-1
	SEPTIN9	ENST00000329047.13	TSL:1 MANE Plus Clinical	c.299_300delAGinsCC	p.Gln100Pro	missense	N/A	ENSP00000329161.8	Q9UHD8-2
	SEPTIN9	ENST00000423034.6	TSL:1	c.332_333delAGinsCC	p.Gln111Pro	missense	N/A	ENSP00000405877.1	Q9UHD8-5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

GnomAD MNV AF: 0.000293 AC: 81 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	not specified (2)
-	1	-	Amyotrophic neuralgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=199/101	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555659856; hg19: chr17-75398417;