17-77402298-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000427674.6(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
ENST00000427674.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.23

Publications

20 publications found

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]

SEPTIN9 Gene-Disease associations (from GenCC):

amyotrophic neuralgia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
neuralgic amyotrophy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

SEPTIN9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 5863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN9	NM_001113491.2 link	c.316C>T	p.Arg106Trp	missense_variant	Exon 3 of 12	ENST00000427177.6	NP_001106963.1	Q9UHD8-1
SEPTIN9	NM_006640.5 link	c.262C>T	p.Arg88Trp	missense_variant	Exon 2 of 11	ENST00000329047.13	NP_006631.2	Q9UHD8-2A0A0S2Z5A5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN9	ENST00000427177.6 link	c.316C>T	p.Arg106Trp	missense_variant	Exon 3 of 12	1	NM_001113491.2	ENSP00000391249.1		Q9UHD8-1
SEPTIN9	ENST00000329047.13 link	c.262C>T	p.Arg88Trp	missense_variant	Exon 2 of 11	1	NM_006640.5	ENSP00000329161.8		Q9UHD8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460356

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726540

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111768

Other (OTH)

AF:

0.00

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Mar 07, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_Moderate, PS4, PM2, PM6, PP3, PP1_Strong -

May 19, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 10, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS4,PS3_MOD,PP1_MOD,PS2_SUP,PM2_SUP -

not provided

Pathogenic:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 17, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published 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) -

May 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SEPT9 function (PMID: 17546647). Advanced 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. 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). -

Aug 23, 2019

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not 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. -

Inborn genetic diseases

Pathogenic:1

Dec 13, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The 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

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

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

LIST_S2

Pathogenic

0.98

D;D;D;D;.;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.73

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.8

.;M;.;.;.;.;.;.

PhyloP100

1.2

PrimateAI

Uncertain

0.74

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

GERP RS

3.1

Varity_R

0.20

gMVP

0.41

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over