17-58526791-C-G

Position:

chr17-58526791-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001368771.2(SEPTIN4):c.1802G>C(p.Arg601Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,613,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R601Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

SEPTIN4
NM_001368771.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61

Variant links:

Genes affected

SEPTIN4 (HGNC:9165): (septin 4) This gene is a member of the septin family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins are highly conserved in yeast, Drosophila, and mouse, and appear to regulate cytoskeletal organization. Disruption of septin function disturbs cytokinesis and results in large multinucleate or polyploid cells. This gene is highly expressed in brain and heart. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. One of the isoforms (known as ARTS) is distinct; it is localized to the mitochondria, and has a role in apoptosis and cancer. [provided by RefSeq, Nov 2010]

SEPTIN4 links:

SEPTIN4-AS1 (HGNC:51345): (SEPTIN4 antisense RNA 1)

SEPTIN4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1686571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEPTIN4	NM_001368771.2 linkuse as main transcript	c.1802G>C	p.Arg601Pro	missense_variant	4/14	ENST00000672673.2
SEPTIN4-AS1	NR_110810.1 linkuse as main transcript	n.258+974C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEPTIN4	ENST00000672673.2 linkuse as main transcript	c.1802G>C	p.Arg601Pro	missense_variant	4/14		NM_001368771.2	P1	O43236-7
SEPTIN4-AS1	ENST00000580589.5 linkuse as main transcript	n.258+974C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000565

AC:

AN:

247878

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134476

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000994

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000163

AC:

238

AN:

1461490

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000203

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000325

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.248G>C (p.R83P) alteration is located in exon 2 (coding exon 2) of the SEPT4 gene. This alteration results from a G to C substitution at nucleotide position 248, causing the arginine (R) at amino acid position 83 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

.;.;T;.;.;.;.;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.54

T;T;T;T;.;T;T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.17

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.34

.;.;N;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;N;N;N;N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.80

N;N;N;.;N;N;.;.

REVEL

Benign

0.076

Sift

Benign

0.14

T;T;T;.;T;T;.;.

Sift4G

Benign

0.26

T;T;T;T;T;T;.;.

Polyphen

0.14

B;P;B;P;B;B;.;.

Vest4

0.40

MVP

0.74

MPC

1.1

ClinPred

0.11

GERP RS

5.0

Varity_R

0.33

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over