17-58520449-T-C

Variant names:

• chr17-58520449-T-C
• NM_001368771.2:c.2968A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001368771.2(SEPTIN4):​c.2968A>G​(p.Lys990Glu) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K990R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SEPTIN4 NM_001368771.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.164
• Publications: 0 publications found

Genes affected

SEPTIN4 (HGNC:9165): (septin 4) This gene is a member of the septin family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins are highly conserved in yeast, Drosophila, and mouse, and appear to regulate cytoskeletal organization. Disruption of septin function disturbs cytokinesis and results in large multinucleate or polyploid cells. This gene is highly expressed in brain and heart. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. One of the isoforms (known as ARTS) is distinct; it is localized to the mitochondria, and has a role in apoptosis and cancer. [provided by RefSeq, Nov 2010]

SEPTIN4-AS1 (HGNC:51345): (SEPTIN4 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036068827).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368771.2. 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
	SEPTIN4	NM_001368771.2	MANE Select	c.2968A>G	p.Lys990Glu	missense	Exon 14 of 14	NP_001355700.1	O43236-7
	SEPTIN4	NM_001256782.2		c.1459A>G	p.Lys487Glu	missense	Exon 13 of 13	NP_001243711.1	O43236-4
	SEPTIN4	NM_004574.5		c.1414A>G	p.Lys472Glu	missense	Exon 12 of 12	NP_004565.1	O43236-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN4	ENST00000672673.2	MANE Select	c.2968A>G	p.Lys990Glu	missense	Exon 14 of 14	ENSP00000500383.1	O43236-7
	SEPTIN4	ENST00000317268.7	TSL:1	c.1414A>G	p.Lys472Glu	missense	Exon 12 of 12	ENSP00000321674.3	O43236-1
	SEPTIN4	ENST00000317256.10	TSL:1	c.1357A>G	p.Lys453Glu	missense	Exon 12 of 12	ENSP00000321071.6	O43236-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

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	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.95	N
PhyloP100		0.16
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.099
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.27		Loss of MoRF binding (P = 0.0031)
MVP		0.45
MPC		0.59
ClinPred		0.12	T
GERP RS		4.6
Varity_R		0.082
gMVP		0.23

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: chr17-56597810;