22-41986065-G-A

Variant names:

• chr22-41986065-G-A
• rs200659820
• NM_001363845.2:c.1778G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001363845.2(SEPTIN3):​c.1778G>A​(p.Arg593Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SEPTIN3 NM_001363845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

Genes affected

SEPTIN3 (HGNC:10750): (septin 3) This gene belongs to the septin family of GTPases. Members of this family are required for cytokinesis. Expression is upregulated by retinoic acid in a human teratocarcinoma cell line. The specific function of this gene has not been determined. Alternative splicing of this gene results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2018]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15421167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN3	NM_001363845.2	c.1778G>A	p.Arg593Gln	missense_variant	Exon 4 of 12	ENST00000644076.2	NP_001350774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN3	ENST00000644076.2	c.1778G>A	p.Arg593Gln	missense_variant	Exon 4 of 12		NM_001363845.2	ENSP00000494051.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251230 AF XY: 0.0000147

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461454 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727014

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33466

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44716

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26128

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39688

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86212

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53386

Gnomad4 NFE exome AF: 0.00000360 AC: 4 AN: 1111812

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

Gnomad4 AFR AF: 0.0000483 AC: 0.0000482602 AN: 0.0000482602

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000293962 AN: 0.0000293962

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.284G>A (p.R95Q) alteration is located in exon 3 (coding exon 3) of the SEPT3 gene. This alteration results from a G to A substitution at nucleotide position 284, causing the arginine (R) at amino acid position 95 to be replaced by a glutamine (Q). 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	0.096
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.017	.;T;T;T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.38	.;.;N;.;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.15	.;N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.36	.;T;T;T;T
Sift4G	Benign	0.38	.;T;T;T;T
Polyphen		0.022, 0.090, 0.017	.;.;B;B;B
Vest4		0.45, 0.40, 0.40
MVP		0.62
MPC		1.3
ClinPred		0.40	T
GERP RS		3.7
Varity_R		0.23
gMVP		0.83
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs200659820; hg19: chr22-42382069;