rs3765043

Variant names:

• chr17-77487446-C-T
• rs3765043
• NM_001113491.2:c.936C>T

Variant summary

Our verdict is Benign. The variant received -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:8
• Conservation: PhyloP100: 0.670
• Publications: 3 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• neuralgic amyotrophy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 325552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113491.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN9	NM_001113491.2	MANE Select	c.936C>T	p.Ser312Ser	synonymous	Exon 5 of 12	NP_001106963.1	Q9UHD8-1
	SEPTIN9	NM_006640.5	MANE Plus Clinical	c.882C>T	p.Ser294Ser	synonymous	Exon 4 of 11	NP_006631.2	Q9UHD8-2
	SEPTIN9	NM_001113493.2		c.915C>T	p.Ser305Ser	synonymous	Exon 4 of 11	NP_001106965.1	Q9UHD8-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN9	ENST00000427177.6	TSL:1 MANE Select	c.936C>T	p.Ser312Ser	synonymous	Exon 5 of 12	ENSP00000391249.1	Q9UHD8-1
	SEPTIN9	ENST00000329047.13	TSL:1 MANE Plus Clinical	c.882C>T	p.Ser294Ser	synonymous	Exon 4 of 11	ENSP00000329161.8	Q9UHD8-2
	SEPTIN9	ENST00000423034.6	TSL:1	c.915C>T	p.Ser305Ser	synonymous	Exon 4 of 11	ENSP00000405877.1	Q9UHD8-5

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

GnomAD2 exomes AF: 0.0102 AC: 2399 AN: 235848 AF XY: 0.00943

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 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

African (AFR) AF: 0.0244 AC: 812 AN: 33298

American (AMR) AF: 0.00108 AC: 47 AN: 43448

Ashkenazi Jewish (ASJ) AF: 0.000886 AC: 23 AN: 25974

East Asian (EAS) AF: 0.0844 AC: 3314 AN: 39264

South Asian (SAS) AF: 0.00546 AC: 464 AN: 84942

European-Finnish (FIN) AF: 0.0145 AC: 759 AN: 52504

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5760

European-Non Finnish (NFE) AF: 0.000475 AC: 527 AN: 1109096

Other (OTH) AF: 0.00587 AC: 353 AN: 60114

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

African (AFR) AF: 0.0236 AC: 982 AN: 41554

American (AMR) AF: 0.00294 AC: 45 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.0782 AC: 404 AN: 5166

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4824

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68014

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00429 Hom.: 19

Bravo AF: 0.0120

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Amyotrophic neuralgia (2)
-	-	2	not specified (2)
-	-	1	SEPTIN9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=74/26	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3765043; hg19: chr17-75483528;