17-77281529-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001113491.2(SEPTIN9):c.-7A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 1,548,048 control chromosomes in the GnomAD database, including 9,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2799 hom., cov: 33)
  • Exomes 𝑓: 0.087 (6636 hom.)
• Consequence: SEPTIN9 NM_001113491.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.353

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-DT (HGNC:52818): (SEPTIN9 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 17-77281529-A-C is Benign according to our data. Variant chr17-77281529-A-C is described in ClinVar as [Benign]. Clinvar id is 1239714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-77281529-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPTIN9	NM_001113491.2	c.-7A>C		5_prime_UTR_variant	1/12	ENST00000427177.6
SEPTIN9-DT	NR_136503.1	n.286+83T>G		intron_variant, non_coding_transcript_variant
SEPTIN9	NM_001293695.2	c.-7A>C		5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPTIN9	ENST00000427177.6	c.-7A>C		5_prime_UTR_variant	1/12	1	NM_001113491.2	A1
SEPTIN9-DT	ENST00000701682.1	n.443+83T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22901 AN: 151948 Hom.: 2790 Cov.: 33

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0883

Gnomad ASJ AF: 0.0743

Gnomad EAS AF: 0.0869

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0373

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.0871 AC: 12898 AN: 148096 Hom.: 852 AF XY: 0.0887 AC XY: 7092 AN XY: 79990

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.0547

Gnomad ASJ exome AF: 0.0713

Gnomad EAS exome AF: 0.0849

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.0413

Gnomad NFE exome AF: 0.0766

Gnomad OTH exome AF: 0.0814

GnomAD4 exome AF: 0.0866 AC: 120909 AN: 1395986 Hom.: 6636 Cov.: 31 AF XY: 0.0869 AC XY: 59856 AN XY: 688908

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.0590

Gnomad4 ASJ exome AF: 0.0704

Gnomad4 EAS exome AF: 0.0715

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.0442

Gnomad4 NFE exome AF: 0.0794

Gnomad4 OTH exome AF: 0.0996

GnomAD4 genome AF: 0.151 AC: 22946 AN: 152062 Hom.: 2799 Cov.: 33 AF XY: 0.148 AC XY: 10992 AN XY: 74368

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.0881

Gnomad4 ASJ AF: 0.0743

Gnomad4 EAS AF: 0.0872

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.0373

Gnomad4 NFE AF: 0.0796

Gnomad4 OTH AF: 0.146

Alfa AF: 0.0906 Hom.: 445

Bravo AF: 0.162

Asia WGS AF: 0.114 AC: 397 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

SEPTIN9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	17
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs8070026; hg19: chr17-75277611; COSMIC: COSV70950037; COSMIC: COSV70950037;