ENST00000427674:c.-59C>T

Variant names:

• chr17-77402416-C-T
• rs34587622
• ENST00000427674.6:c.-59C>T

Variant summary

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

The ENST00000427674.6(SEPTIN9):​c.-59C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,610,262 control chromosomes in the GnomAD database, including 9,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (654 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8384 hom.)
• Consequence: SEPTIN9 ENST00000427674.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.80
• Publications: 34 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=0.0017449558).
• BP6: Variant 17-77402416-C-T is Benign according to our data. Variant chr17-77402416-C-T is described in ClinVar as Benign. ClinVar VariationId is 325543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000427674.6. 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.434C>T	p.Pro145Leu	missense	Exon 3 of 12	NP_001106963.1	Q9UHD8-1
	SEPTIN9	NM_006640.5	MANE Plus Clinical	c.380C>T	p.Pro127Leu	missense	Exon 2 of 11	NP_006631.2	Q9UHD8-2
	SEPTIN9	NM_001113492.2		c.-59C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	NP_001106964.1	Q9UHD8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN9	ENST00000427674.6	TSL:1	c.-59C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000403194.1	Q9UHD8-3
	SEPTIN9	ENST00000427177.6	TSL:1 MANE Select	c.434C>T	p.Pro145Leu	missense	Exon 3 of 12	ENSP00000391249.1	Q9UHD8-1
	SEPTIN9	ENST00000329047.13	TSL:1 MANE Plus Clinical	c.380C>T	p.Pro127Leu	missense	Exon 2 of 11	ENSP00000329161.8	Q9UHD8-2

Frequencies

GnomAD3 genomes AF: 0.0810 AC: 12326 AN: 152148 Hom.: 655 Cov.: 32

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0870

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.0685

Gnomad FIN AF: 0.0620

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.0834 AC: 19985 AN: 239538 AF XY: 0.0857

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.0707

Gnomad ASJ exome AF: 0.0806

Gnomad EAS exome AF: 0.00472

Gnomad FIN exome AF: 0.0668

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.103 AC: 149545 AN: 1457996 Hom.: 8384 Cov.: 33 AF XY: 0.103 AC XY: 74348 AN XY: 725068

African (AFR) AF: 0.0197 AC: 659 AN: 33440

American (AMR) AF: 0.0725 AC: 3217 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 2094 AN: 26040

East Asian (EAS) AF: 0.0263 AC: 1040 AN: 39612

South Asian (SAS) AF: 0.0689 AC: 5909 AN: 85822

European-Finnish (FIN) AF: 0.0683 AC: 3559 AN: 52118

Middle Eastern (MID) AF: 0.133 AC: 766 AN: 5760

European-Non Finnish (NFE) AF: 0.114 AC: 126341 AN: 1110644

Other (OTH) AF: 0.0990 AC: 5960 AN: 60186

GnomAD4 genome AF: 0.0810 AC: 12329 AN: 152266 Hom.: 654 Cov.: 32 AF XY: 0.0791 AC XY: 5890 AN XY: 74456

African (AFR) AF: 0.0214 AC: 891 AN: 41566

American (AMR) AF: 0.107 AC: 1635 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0870 AC: 302 AN: 3470

East Asian (EAS) AF: 0.0137 AC: 71 AN: 5178

South Asian (SAS) AF: 0.0675 AC: 326 AN: 4828

European-Finnish (FIN) AF: 0.0620 AC: 659 AN: 10622

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7916 AN: 67992

Other (OTH) AF: 0.109 AC: 229 AN: 2108

Alfa AF: 0.100 Hom.: 1385

Bravo AF: 0.0813

TwinsUK AF: 0.112 AC: 416

ALSPAC AF: 0.111 AC: 429

ESP6500AA AF: 0.0231 AC: 100

ESP6500EA AF: 0.112 AC: 953

ExAC AF: 0.0811 AC: 9811

Asia WGS AF: 0.0480 AC: 168 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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.060
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.037	D
Polyphen		0.86	P
Vest4		0.18
MPC		0.15
ClinPred		0.025	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.13
Mutation Taster		=98/2	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: rs34587622; hg19: chr17-75398498; COSMIC: COSV61204988; COSMIC: COSV61204988;