rs34587622

Positions:

• chr17-77402416-C-G
• chr17-77402416-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001113491.2(SEPTIN9):​c.434C>G​(p.Pro145Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. P145L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEPTIN9 NM_001113491.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22001076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEPTIN9	NM_001113491.2	c.434C>G	p.Pro145Arg	missense_variant	3/12	ENST00000427177.6	NP_001106963.1
SEPTIN9	NM_006640.5	c.380C>G	p.Pro127Arg	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.434C>G	p.Pro145Arg	missense_variant	3/12	1	NM_001113491.2	ENSP00000391249	A1
SEPTIN9	ENST00000329047.13	c.380C>G	p.Pro127Arg	missense_variant	2/11	1	NM_006640.5	ENSP00000329161	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	T;.;.;.;.;.;T
Eigen	Benign	0.016
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N;.;N;.;.;N;.
REVEL	Benign	0.094
Sift	Uncertain	0.0010	D;.;D;.;.;D;.
Sift4G	Uncertain	0.039	D;T;T;T;D;D;D
Polyphen		0.73	P;D;D;D;.;D;.
Vest4		0.41
MutPred		0.34		Gain of MoRF binding (P = 4e-04);.;.;.;.;.;.;
MVP		0.43
MPC		0.49
ClinPred		0.88	D
GERP RS		4.3
Varity_R		0.090
gMVP		0.18

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: rs34587622; hg19: chr17-75398498;