22-41989683-G-A

Variant names:

• chr22-41989683-G-A
• NM_001363845.2:c.2162G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001363845.2(SEPTIN3):​c.2162G>A​(p.Arg721Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SEPTIN3 NM_001363845.2 missense, splice_region
• Scores: Splicing: ADA: 0.9658
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN3	NM_001363845.2	c.2162G>A	p.Arg721Lys	missense_variant, splice_region_variant	Exon 7 of 12	ENST00000644076.2	NP_001350774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN3	ENST00000644076.2	c.2162G>A	p.Arg721Lys	missense_variant, splice_region_variant	Exon 7 of 12		NM_001363845.2	ENSP00000494051.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668G>A (p.R223K) alteration is located in exon 6 (coding exon 6) of the SEPT3 gene. This alteration results from a G to A substitution at nucleotide position 668, causing the arginine (R) at amino acid position 223 to be replaced by a lysine (K). 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	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.1	.;L;.;L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.7	.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.29	.;T;T;T
Sift4G	Benign	0.35	.;T;T;T
Polyphen		0.98, 0.047, 0.97	.;D;B;D
Vest4		0.26, 0.26, 0.26
MutPred		0.61		.;Loss of ubiquitination at K226 (P = 0.0756);.;Loss of ubiquitination at K226 (P = 0.0756);
MVP		0.69
MPC		0.95
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.60
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.63
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-42385687;