22-41987267-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN3	NM_001363845.2	c.1887C>G	p.Asp629Glu	missense_variant	Exon 5 of 12	ENST00000644076.2	NP_001350774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN3	ENST00000644076.2	c.1887C>G	p.Asp629Glu	missense_variant	Exon 5 of 12		NM_001363845.2	ENSP00000494051.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.393C>G (p.D131E) alteration is located in exon 4 (coding exon 4) of the SEPT3 gene. This alteration results from a C to G substitution at nucleotide position 393, causing the aspartic acid (D) at amino acid position 131 to be replaced by a glutamic acid (E). 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	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;D;T;.
Eigen	Benign	0.097
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.5	.;.;M;.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.0	.;D;D;D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.016	.;D;D;D;D
Polyphen		0.049, 0.99, 0.040	.;.;B;D;B
Vest4		0.75, 0.75, 0.75
MutPred		0.91		.;.;Loss of helix (P = 0.1706);.;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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-42383271;