chr17-77498623-A-G

Variant names:

• chr17-77498623-A-G
• rs2627223
• NM_001113491.2:c.1726A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001113491.2(SEPTIN9):​c.1726A>G​(p.Met576Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 1,605,190 control chromosomes in the GnomAD database, including 698,432 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M576A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.90 (59868 hom., cov: 22)
  • Exomes 𝑓: 0.94 (638564 hom.)
• Consequence: SEPTIN9 NM_001113491.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0700
• Publications: 41 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.6784125E-7).
• BP6: Variant 17-77498623-A-G is Benign according to our data. Variant chr17-77498623-A-G is described in ClinVar as Benign. ClinVar VariationId is 325568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.1726A>G	p.Met576Val	missense	Exon 12 of 12	NP_001106963.1	Q9UHD8-1
	SEPTIN9	NM_006640.5	MANE Plus Clinical	c.1672A>G	p.Met558Val	missense	Exon 11 of 11	NP_006631.2	Q9UHD8-2
	SEPTIN9	NM_001113493.2		c.1705A>G	p.Met569Val	missense	Exon 11 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.1726A>G	p.Met576Val	missense	Exon 12 of 12	ENSP00000391249.1	Q9UHD8-1
	SEPTIN9	ENST00000329047.13	TSL:1 MANE Plus Clinical	c.1672A>G	p.Met558Val	missense	Exon 11 of 11	ENSP00000329161.8	Q9UHD8-2
	SEPTIN9	ENST00000423034.6	TSL:1	c.1705A>G	p.Met569Val	missense	Exon 11 of 11	ENSP00000405877.1	Q9UHD8-5

Frequencies

GnomAD3 genomes AF: 0.897 AC: 132362 AN: 147624 Hom.: 59837 Cov.: 22

Gnomad AFR AF: 0.775

Gnomad AMI AF: 0.945

Gnomad AMR AF: 0.947

Gnomad ASJ AF: 0.953

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.924

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.921

GnomAD2 exomes AF: 0.939 AC: 228894 AN: 243712 AF XY: 0.942

Gnomad AFR exome AF: 0.770

Gnomad AMR exome AF: 0.967

Gnomad ASJ exome AF: 0.950

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.923

Gnomad NFE exome AF: 0.937

Gnomad OTH exome AF: 0.949

GnomAD4 exome AF: 0.936 AC: 1363551 AN: 1457456 Hom.: 638564 Cov.: 39 AF XY: 0.937 AC XY: 679450 AN XY: 724910

African (AFR) AF: 0.775 AC: 25862 AN: 33362

American (AMR) AF: 0.964 AC: 42923 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 24755 AN: 26058

East Asian (EAS) AF: 1.00 AC: 39562 AN: 39578

South Asian (SAS) AF: 0.970 AC: 83219 AN: 85776

European-Finnish (FIN) AF: 0.923 AC: 48438 AN: 52462

Middle Eastern (MID) AF: 0.964 AC: 5313 AN: 5514

European-Non Finnish (NFE) AF: 0.934 AC: 1037275 AN: 1110028

Other (OTH) AF: 0.934 AC: 56204 AN: 60154

GnomAD4 genome AF: 0.896 AC: 132443 AN: 147734 Hom.: 59868 Cov.: 22 AF XY: 0.899 AC XY: 64499 AN XY: 71782

African (AFR) AF: 0.775 AC: 30783 AN: 39728

American (AMR) AF: 0.948 AC: 14167 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.953 AC: 3292 AN: 3456

East Asian (EAS) AF: 0.999 AC: 4809 AN: 4812

South Asian (SAS) AF: 0.969 AC: 4547 AN: 4692

European-Finnish (FIN) AF: 0.924 AC: 8686 AN: 9398

Middle Eastern (MID) AF: 0.966 AC: 280 AN: 290

European-Non Finnish (NFE) AF: 0.936 AC: 63123 AN: 67436

Other (OTH) AF: 0.920 AC: 1902 AN: 2068

Alfa AF: 0.916 Hom.: 81734

Bravo AF: 0.893

TwinsUK AF: 0.933 AC: 3461

ALSPAC AF: 0.937 AC: 3610

ESP6500AA AF: 0.798 AC: 3399

ESP6500EA AF: 0.940 AC: 7971

ExAC AF: 0.934 AC: 112299

Asia WGS AF: 0.962 AC: 3343 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Amyotrophic neuralgia (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.22
DANN	Benign	0.33
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.092	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.4	N
PhyloP100		0.070
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.049
Sift	Benign	1.0	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.61
ClinPred		0.0013	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs2627223; hg19: chr17-75494705; COSMIC: COSV61208733; COSMIC: COSV61208733;