chr17-77402298-C-T

Position:

• chr17-77402298-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 1.23

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 (HGNC:):

ACMG classification

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
SEPTIN9	NM_001113491.2	c.316C>T	p.Arg106Trp	missense_variant	3/12	ENST00000427177.6	NP_001106963.1
SEPTIN9	NM_006640.5	c.262C>T	p.Arg88Trp	missense_variant	2/11	ENST00000329047.13	NP_006631.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEPTIN9	ENST00000427177.6	c.316C>T	p.Arg106Trp	missense_variant	3/12	1	NM_001113491.2	ENSP00000391249.1
SEPTIN9	ENST00000329047.13	c.262C>T	p.Arg88Trp	missense_variant	2/11	1	NM_006640.5	ENSP00000329161.8

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

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:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic neuralgia Pathogenic:4 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, 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 provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 07, 2024	PS3_Moderate, PS4, PM2, PM6, PP3, PP1_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 10, 2024	Criteria applied: PS4,PS3_MOD,PP1_MOD,PS2_SUP,PM2_SUP -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 19, 2009	- -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 23, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 01, 2023	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. 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 submitter

clinical testing

Ambry Genetics

Dec 13, 2022

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	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

Other links and lift over

dbSNP: rs80338761; hg19: chr17-75398380;