rs61744333

chr17-77402183-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001113491.2(SEPTIN9):c.201C>T(p.Gly67=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,790 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: SEPTIN9 NM_001113491.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.50

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-77402183-C-T is Benign according to our data. Variant chr17-77402183-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 325539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-77402183-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS2: High AC in GnomAd at 325 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPTIN9	NM_001113491.2	c.201C>T	p.Gly67=	synonymous_variant	3/12	ENST00000427177.6
SEPTIN9	NM_006640.5	c.147C>T	p.Gly49=	synonymous_variant	2/11	ENST00000329047.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPTIN9	ENST00000427177.6	c.201C>T	p.Gly67=	synonymous_variant	3/12	1	NM_001113491.2	A1
SEPTIN9	ENST00000329047.13	c.147C>T	p.Gly49=	synonymous_variant	2/11	1	NM_006640.5	P3

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00202 AC: 503 AN: 248798 Hom.: 0 AF XY: 0.00210 AC XY: 284 AN XY: 135112

Gnomad AFR exome AF: 0.000972

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00288 AC: 4213 AN: 1461550 Hom.: 4 Cov.: 32 AF XY: 0.00290 AC XY: 2111 AN XY: 727060

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00336

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74432

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00261 Hom.: 0

Bravo AF: 0.00226

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SEPTIN9: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2016	- -

Amyotrophic neuralgia Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	5.6
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61744333; hg19: chr17-75398265; COSMIC: COSV61203236; COSMIC: COSV61203236;