rs80338761

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001113492.2(SEPTIN9):​c.-177C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SEPTIN9
NM_001113492.2 5_prime_UTR_premature_start_codon_gain

Scores

7
6
6

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:2

Conservation

PhyloP100: 1.23
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-77402298-C-T is Pathogenic according to our data. Variant chr17-77402298-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-77402298-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SEPTIN9NM_001113491.2 linkuse as main transcriptc.316C>T p.Arg106Trp missense_variant 3/12 ENST00000427177.6 NP_001106963.1 Q9UHD8-1
SEPTIN9NM_006640.5 linkuse as main transcriptc.262C>T p.Arg88Trp missense_variant 2/11 ENST00000329047.13 NP_006631.2 Q9UHD8-2A0A0S2Z5A5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SEPTIN9ENST00000427177.6 linkuse as main transcriptc.316C>T p.Arg106Trp missense_variant 3/121 NM_001113491.2 ENSP00000391249.1 Q9UHD8-1
SEPTIN9ENST00000329047.13 linkuse as main transcriptc.262C>T p.Arg88Trp missense_variant 2/111 NM_006640.5 ENSP00000329161.8 Q9UHD8-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460356
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726540
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Amyotrophic neuralgia Pathogenic:4Other:2
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant classified as Pathogenic and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterMar 07, 2024PS3_Moderate, PS4, PM2, PM6, PP3, PP1_Strong -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJun 10, 2024Criteria applied: PS4,PS3_MOD,PP1_MOD,PS2_SUP,PM2_SUP -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 19, 2009- -
not provided Pathogenic:5
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 17, 2023Published functional studies demonstrate a damaging effect resulting in likely altered interactions with partner molecules and lack of response to Rhotekin signaling (Sudo et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19451530, 16186812, 30019529, 31619932, 18492087, 19204161, 20019224, 22981636, 27535533, 17546647, 28503616) -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsAug 23, 2019Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 01, 2023Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SEPT9 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SEPT9 function (PMID: 17546647). ClinVar contains an entry for this variant (Variation ID: 5863). This missense change has been observed in individual(s) with hereditary neuralgic amyotrophy (PMID: 16186812, 18492087, 19204161, 20019224, 22981636, 28503616, 31619932). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 88 of the SEPT9 protein (p.Arg88Trp). -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 13, 2022The c.262C>T (p.R88W) alteration is located in coding exon 2 of the SEPT9 gene. This alteration results from a C to T substitution at nucleotide position 262, causing the arginine (R) at amino acid position 88 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple families with hereditary neuralgic amyotrophy (Kuhlenbäumer, 2005; Laccone, 2008; Hannibal, 2009; Klein, 2009; Ueda, 2010; Leshinsky-Silver, 2013; Chuk, 2016; Serin, 2019). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.R88W alteration alters the interaction of septin-9 with partner molecules (Sudo, 2007). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.14
.;T;.;.;.;T;.;T
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.14
FATHMM_MKL
Benign
0.68
D
LIST_S2
Pathogenic
0.98
D;D;D;D;.;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.73
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.74
T
MutationAssessor
Uncertain
2.8
.;M;.;.;.;.;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.0
.;N;.;N;.;.;N;.
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
.;D;.;D;.;.;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;D;D;.;D;.
Vest4
0.83, 0.80, 0.87, 0.88, 0.83
MutPred
0.63
.;Loss of glycosylation at S105 (P = 0.0306);.;.;.;.;.;.;
MVP
0.96
MPC
0.49
ClinPred
0.98
D
GERP RS
3.1
Varity_R
0.20
gMVP
0.41

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338761; hg19: chr17-75398380; API