Genetic Variant SEPTIN7:p.Thr228Ala (chr7-35882535-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001788.6(SEPTIN7):c.682A>G(p.Thr228Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SEPTIN7
NM_001788.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.57

Publications

1 publications found

Variant links:

Genes affected

SEPTIN7 (HGNC:1717): (septin 7) This gene encodes a protein that is highly similar to the CDC10 protein of Saccharomyces cerevisiae. The protein also shares similarity with Diff 6 of Drosophila and with H5 of mouse. Each of these similar proteins, including the yeast CDC10, contains a GTP-binding motif. The yeast CDC10 protein is a structural component of the 10 nm filament which lies inside the cytoplasmic membrane and is essential for cytokinesis. This human protein functions in gliomagenesis and in the suppression of glioma cell growth, and it is required for the association of centromere-associated protein E with the kinetochore. Alternative splicing results in multiple transcript variants. Several related pseudogenes have been identified on chromosomes 5, 7, 9, 10, 11, 14, 17 and 19. [provided by RefSeq, Jul 2011]

SEPTIN7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a modified_residue Phosphothreonine (size 0) in uniprot entity SEPT7_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1396308).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN7	NM_001788.6 link	c.682A>G	p.Thr228Ala	missense_variant	Exon 8 of 14	ENST00000350320.11	NP_001779.3	Q16181-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SEPTIN7	ENST00000350320.11 link	c.682A>G	p.Thr228Ala	missense_variant	Exon 8 of 14	5	NM_001788.6	ENSP00000344868.8	Q16181-1E7EPK1
SEPTIN7	ENST00000635175.1 link	n.*599A>G		non_coding_transcript_exon_variant	Exon 8 of 14	2		ENSP00000489192.1	A0A0U1RQW0
SEPTIN7	ENST00000635175.1 link	n.*599A>G		3_prime_UTR_variant	Exon 8 of 14	2		ENSP00000489192.1	A0A0U1RQW0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000738

AC:

AN:

135512

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1336440

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

657006

African (AFR)

AF:

0.00

AC:

AN:

28832

American (AMR)

AF:

0.00

AC:

AN:

29294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23236

East Asian (EAS)

AF:

0.00

AC:

AN:

33414

South Asian (SAS)

AF:

0.00

AC:

AN:

74304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5396

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1040970

Other (OTH)

AF:

0.00

AC:

AN:

54758

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 02, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.682A>G (p.T228A) alteration is located in exon 8 (coding exon 8) of the SEPT7 gene. This alteration results from a A to G substitution at nucleotide position 682, causing the threonine (T) at amino acid position 228 to be replaced by an alanine (A). 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

0.091

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.033

.;T;T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.026

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.72

PhyloP100

5.6

PrimateAI

Uncertain

0.76

REVEL

Benign

0.19

Sift4G

Benign

0.52

T;T;T;T

Vest4

0.20

MutPred

0.37

.;Loss of phosphorylation at T228 (P = 0.0171);.;.;

MVP

0.94

MPC

0.73

ClinPred

0.32

GERP RS

4.0

gMVP

0.58

Mutation Taster

=43/57

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over