rs768871202

Variant names:

• chr17-77490817-G-A
• rs768871202
• NM_001113491.2:c.1338G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-77490817-G-A
• chr17-77490817-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001113491.2(SEPTIN9):​c.1338G>A​(p.Ala446Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000728 in 1,594,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A446A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: SEPTIN9 NM_001113491.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.60
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-77490817-G-A is Benign according to our data. Variant chr17-77490817-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 325561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.6 with no splicing effect.
• BS2: High AC in GnomAd4 at 6 AD gene.

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.1338G>A	p.Ala446Ala	synonymous	Exon 8 of 12	NP_001106963.1
	SEPTIN9	NM_006640.5	MANE Plus Clinical	c.1284G>A	p.Ala428Ala	synonymous	Exon 7 of 11	NP_006631.2
	SEPTIN9	NM_001113493.2		c.1317G>A	p.Ala439Ala	synonymous	Exon 7 of 11	NP_001106965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN9	ENST00000427177.6	TSL:1 MANE Select	c.1338G>A	p.Ala446Ala	synonymous	Exon 8 of 12	ENSP00000391249.1
	SEPTIN9	ENST00000329047.13	TSL:1 MANE Plus Clinical	c.1284G>A	p.Ala428Ala	synonymous	Exon 7 of 11	ENSP00000329161.8
	SEPTIN9	ENST00000423034.6	TSL:1	c.1317G>A	p.Ala439Ala	synonymous	Exon 7 of 11	ENSP00000405877.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 38 AN: 217016 AF XY: 0.000187

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000319

Gnomad ASJ exome AF: 0.00257

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000934

Gnomad OTH exome AF: 0.000727

GnomAD4 exome AF: 0.0000763 AC: 110 AN: 1442170 Hom.: 0 Cov.: 31 AF XY: 0.0000824 AC XY: 59 AN XY: 715590

African (AFR) AF: 0.0000302 AC: 1 AN: 33102

American (AMR) AF: 0.0000237 AC: 1 AN: 42148

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 61 AN: 25682

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38780

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51758

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5746

European-Non Finnish (NFE) AF: 0.0000191 AC: 21 AN: 1102346

Other (OTH) AF: 0.000251 AC: 15 AN: 59678

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74394

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Amyotrophic neuralgia (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.5
DANN	Benign	0.68
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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

Other links and lift over

dbSNP: rs768871202; hg19: chr17-75486899; COSMIC: COSV100218459; COSMIC: COSV100218459;