rs1373809087

Variant names:

• chr22-41987645-T-C
• rs1373809087
• NM_001363845.2:c.1931T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001363845.2(SEPTIN3):​c.1931T>C​(p.Ile644Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SEPTIN3 NM_001363845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.94
• Publications: 0 publications found

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363845.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN3	NM_001363845.2	MANE Select	c.1931T>C	p.Ile644Thr	missense	Exon 6 of 12	NP_001350774.1	A0A2R8Y4H2
	SEPTIN3	NM_001389668.1		c.1931T>C	p.Ile644Thr	missense	Exon 6 of 11	NP_001376597.1
	SEPTIN3	NM_001389669.1		c.1802T>C	p.Ile601Thr	missense	Exon 5 of 11	NP_001376598.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN3	ENST00000644076.2	MANE Select	c.1931T>C	p.Ile644Thr	missense	Exon 6 of 12	ENSP00000494051.1	A0A2R8Y4H2
	SEPTIN3	ENST00000396426.7	TSL:1	c.437T>C	p.Ile146Thr	missense	Exon 5 of 11	ENSP00000379704.3	Q9UH03-1
	SEPTIN3	ENST00000396425.8	TSL:1	c.437T>C	p.Ile146Thr	missense	Exon 5 of 10	ENSP00000379703.3	Q9UH03-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461240 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726830

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111500

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.82		Gain of disorder (P = 0.0259)
MVP		0.84
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.94
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs1373809087; hg19: chr22-42383649;