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 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

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: PanelApp Australia, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113492.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEPTIN9	NM_001113491.2	MANE Select	c.316C>T	p.Arg106Trp	missense	Exon 3 of 12	NP_001106963.1	Q9UHD8-1
SEPTIN9	NM_006640.5	MANE Plus Clinical	c.262C>T	p.Arg88Trp	missense	Exon 2 of 11	NP_006631.2	Q9UHD8-2
SEPTIN9	NM_001113492.2		c.-177C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	NP_001106964.1	Q9UHD8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEPTIN9	ENST00000427674.6	TSL:1	c.-177C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000403194.1	Q9UHD8-3
SEPTIN9	ENST00000427177.6	TSL:1 MANE Select	c.316C>T	p.Arg106Trp	missense	Exon 3 of 12	ENSP00000391249.1	Q9UHD8-1
SEPTIN9	ENST00000329047.13	TSL:1 MANE Plus Clinical	c.262C>T	p.Arg88Trp	missense	Exon 2 of 11	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

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Amyotrophic neuralgia (6)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.68

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.8

PhyloP100

1.2

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over