17-77482288-G-T

Variant names:

• chr17-77482288-G-T
• rs587781247
• NM_001113491.2:c.866G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001113491.2(SEPTIN9):​c.866G>T​(p.Arg289Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R289H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SEPTIN9 NM_001113491.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83
• 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: Labcorp Genetics (formerly Invitae)
• neuralgic amyotrophy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN9	NM_001113491.2	c.866G>T	p.Arg289Leu	missense_variant	Exon 4 of 12	ENST00000427177.6	NP_001106963.1
SEPTIN9	NM_006640.5	c.812G>T	p.Arg271Leu	missense_variant	Exon 3 of 11	ENST00000329047.13	NP_006631.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN9	ENST00000427177.6	c.866G>T	p.Arg289Leu	missense_variant	Exon 4 of 12	1	NM_001113491.2	ENSP00000391249.1
SEPTIN9	ENST00000329047.13	c.812G>T	p.Arg271Leu	missense_variant	Exon 3 of 11	1	NM_006640.5	ENSP00000329161.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460912 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726728

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;.;.;.;.;.;T;.;T;.;T;.;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;.;.;D;D;.;D;D;D;D;.;D;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		6.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;.;D;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D;.;D;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T;D;D
Polyphen		0.96	D;D;.;.;D;D;.;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.78
MutPred		0.50		Loss of MoRF binding (P = 0.0301);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.74
MPC		1.6
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.84

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

Other links and lift over

dbSNP: rs587781247; hg19: chr17-75478370;