Genetic Variant SEPTIN6:p.Arg275Gln (chrX-119637159-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4BP6_ModerateBS2

The NM_145799.4(SEPTIN6):c.824G>A(p.Arg275Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,209,986 control chromosomes in the GnomAD database, including 1 homozygotes. There are 103 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00020 ( 1 hom. 94 hem. )

Consequence

SEPTIN6
NM_145799.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

SEPTIN6 (HGNC:15848): (septin 6) This gene is a member of the septin family of GTPases. Members of this family are required for cytokinesis. One version of pediatric acute myeloid leukemia is the result of a reciprocal translocation between chromosomes 11 and X, with the breakpoint associated with the genes encoding the mixed-lineage leukemia and septin 2 proteins. This gene encodes four transcript variants encoding three distinct isoforms. An additional transcript variant has been identified, but its biological validity has not been determined. [provided by RefSeq, Jul 2008]

SEPTIN6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.3500222).

BP6

Variant X-119637159-C-T is Benign according to our data. Variant chrX-119637159-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2661299.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN6	NM_145799.4 link	c.824G>A	p.Arg275Gln	missense_variant	Exon 7 of 11	ENST00000394610.7	NP_665798.1	Q14141-2Q541S4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN6	ENST00000394610.7 link	c.824G>A	p.Arg275Gln	missense_variant	Exon 7 of 11	1	NM_145799.4	ENSP00000378108.1		Q14141-2

Frequencies

GnomAD3 genomes

AF:

0.000232

AC:

AN:

112023

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

AN XY:

34179

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00182

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000263

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000366

AC:

AN:

183301

Hom.:

AF XY:

0.000369

AC XY:

AN XY:

67743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000267

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00200

Gnomad NFE exome

AF:

0.000379

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000202

AC:

222

AN:

1097963

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

AN XY:

363317

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000361

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00180

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000232

AC:

AN:

112023

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

AN XY:

34179

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000377

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00182

Gnomad4 NFE

AF:

0.000263

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000346

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000395

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SEPTIN6: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

.;.;.;T;.;D

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

.;D;.;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.35

T;T;T;T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

4.1

H;H;H;.;H;H

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.4

D;D;D;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

0.90

.;.;.;.;.;P

Vest4

0.94

MVP

0.89

MPC

1.8

ClinPred

0.37

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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