rs3765043

Positions:

• chr17-77487446-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001113491.2(SEPTIN9):​c.936C>T​(p.Ser312Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,606,656 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (159 hom.)
• Consequence: SEPTIN9 NM_001113491.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.670

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 17-77487446-C-T is Benign according to our data. Variant chr17-77487446-C-T is described in ClinVar as [Benign]. Clinvar id is 325552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-77487446-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEPTIN9	NM_001113491.2	c.936C>T	p.Ser312Ser	synonymous_variant	5/12	ENST00000427177.6	NP_001106963.1
SEPTIN9	NM_006640.5	c.882C>T	p.Ser294Ser	synonymous_variant	4/11	ENST00000329047.13	NP_006631.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEPTIN9	ENST00000427177.6	c.936C>T	p.Ser312Ser	synonymous_variant	5/12	1	NM_001113491.2	ENSP00000391249.1
SEPTIN9	ENST00000329047.13	c.882C>T	p.Ser294Ser	synonymous_variant	4/11	1	NM_006640.5	ENSP00000329161.8

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1674 AN: 152138 Hom.: 34 Cov.: 31

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.0102 AC: 2399 AN: 235848 Hom.: 61 AF XY: 0.00943 AC XY: 1211 AN XY: 128370

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.000760

Gnomad ASJ exome AF: 0.00133

Gnomad EAS exome AF: 0.0843

Gnomad SAS exome AF: 0.00479

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00448

GnomAD4 exome AF: 0.00434 AC: 6319 AN: 1454400 Hom.: 159 Cov.: 32 AF XY: 0.00432 AC XY: 3125 AN XY: 722904

Gnomad4 AFR exome AF: 0.0244

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.000886

Gnomad4 EAS exome AF: 0.0844

Gnomad4 SAS exome AF: 0.00546

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.000475

Gnomad4 OTH exome AF: 0.00587

GnomAD4 genome AF: 0.0110 AC: 1679 AN: 152256 Hom.: 34 Cov.: 31 AF XY: 0.0119 AC XY: 883 AN XY: 74450

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.0782

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00300 Hom.: 14

Bravo AF: 0.0120

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Amyotrophic neuralgia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 11, 2017

- -

SEPTIN9-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3765043; hg19: chr17-75483528;