22-41987267-C-G

Variant names:

• chr22-41987267-C-G
• NM_001363845.2:c.1887C>G

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.1887C>G​(p.Asp629Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEPTIN3 NM_001363845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• 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, 0.921

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.1887C>G	p.Asp629Glu	missense	Exon 5 of 12	NP_001350774.1	A0A2R8Y4H2
	SEPTIN3	NM_001389668.1		c.1887C>G	p.Asp629Glu	missense	Exon 5 of 11	NP_001376597.1
	SEPTIN3	NM_001389669.1		c.1758C>G	p.Asp586Glu	missense	Exon 4 of 11	NP_001376598.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN3	ENST00000644076.2	MANE Select	c.1887C>G	p.Asp629Glu	missense	Exon 5 of 12	ENSP00000494051.1	A0A2R8Y4H2
	SEPTIN3	ENST00000396426.7	TSL:1	c.393C>G	p.Asp131Glu	missense	Exon 4 of 11	ENSP00000379704.3	Q9UH03-1
	SEPTIN3	ENST00000396425.8	TSL:1	c.393C>G	p.Asp131Glu	missense	Exon 4 of 10	ENSP00000379703.3	Q9UH03-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	0.97
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.097
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		0.049	B
Vest4		0.75
MutPred		0.91		Loss of helix (P = 0.1706)
MVP		0.80
MPC		1.8
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.87
gMVP		0.90
Mutation Taster		=45/55	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

hg19: chr22-42383271;