Genetic Variant SEPTIN9:c.31+542C>T (chr17-77281348-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000589070.1(SEPTIN9):c.31+542C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 541,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000029 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SEPTIN9
ENST00000589070.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.183

Variant links:

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 links:

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

SEPTIN9-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN9-DT	NR_136503.1 link	n.286+264G>A	intron_variant	Intron 1 of 2
SEPTIN9	NM_001113491.2 link	c.-188C>T	upstream_gene_variant		ENST00000427177.6	NP_001106963.1	Q9UHD8-1
SEPTIN9	NM_001293695.2 link	c.-188C>T	upstream_gene_variant			NP_001280624.1	Q9UHD8-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN9	ENST00000427177.6 link	c.-188C>T		upstream_gene_variant		1	NM_001113491.2	ENSP00000391249.1		Q9UHD8-1

Frequencies

GnomAD3 genomes

AF:

0.0000294

AC:

AN:

136078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000789

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000312

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000296

AC:

AN:

405214

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

213818

show subpopulations

African (AFR)

AF:

0.000367

AC:

AN:

8164

American (AMR)

AF:

0.00

AC:

AN:

12240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12134

East Asian (EAS)

AF:

0.00

AC:

AN:

23628

South Asian (SAS)

AF:

0.0000501

AC:

AN:

39914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1838

European-Non Finnish (NFE)

AF:

0.0000274

AC:

AN:

255440

Other (OTH)

AF:

0.00

AC:

AN:

23358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000294

AC:

AN:

136078

Hom.:

Cov.:

AF XY:

0.0000307

AC XY:

AN XY:

65170

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000275

AC:

AN:

36308

American (AMR)

AF:

0.0000789

AC:

AN:

12678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3328

East Asian (EAS)

AF:

0.00

AC:

AN:

4640

South Asian (SAS)

AF:

0.00

AC:

AN:

4354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7670

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.0000312

AC:

AN:

64028

Other (OTH)

AF:

0.00

AC:

AN:

1930

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.016503), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.0

(source)

DANN

Benign

0.68

PhyloP100

-0.18

PromoterAI

0.13

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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17-77281348-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over