Genetic Variant SEPTIN6:p.Arg370His (chrX-119629489-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_145799.4(SEPTIN6):c.1109G>A(p.Arg370His) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,208,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 7 hem. )

Consequence

SEPTIN6
NM_145799.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.88

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27791405).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN6	NM_145799.4 link	c.1109G>A	p.Arg370His	missense_variant	Exon 9 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.1109G>A	p.Arg370His	missense_variant	Exon 9 of 11	1	NM_145799.4	ENSP00000378108.1		Q14141-2

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111318

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33526

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183188

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67646

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1097424

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

362814

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111318

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33526

show subpopulations

Gnomad4 AFR

AF:

0.0000327

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000282

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1109G>A (p.R370H) alteration is located in exon 9 (coding exon 9) of the SEPT6 gene. This alteration results from a G to A substitution at nucleotide position 1109, causing the arginine (R) at amino acid position 370 to be replaced by a histidine (H). 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

0.083

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.019

.;.;.;T;.;T

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

.;D;.;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.28

T;T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

-0.49

N;N;N;.;N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

1.4

N;N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.97

T;T;T;T;T;T

Sift4G

Benign

0.76

T;T;T;T;T;T

Polyphen

0.0060

.;.;.;.;.;B

Vest4

0.19

MVP

0.89

MPC

1.3

ClinPred

0.27

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.39

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

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