17-58525121-C-A

Variant names:

• chr17-58525121-C-A
• rs1234386380
• NM_001368771.2:c.2173G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001368771.2(SEPTIN4):​c.2173G>T​(p.Val725Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SEPTIN4 NM_001368771.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN4	NM_001368771.2	c.2173G>T	p.Val725Leu	missense_variant	Exon 7 of 14	ENST00000672673.2	NP_001355700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN4	ENST00000672673.2	c.2173G>T	p.Val725Leu	missense_variant	Exon 7 of 14		NM_001368771.2	ENSP00000500383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251468 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.619G>T (p.V207L) alteration is located in exon 5 (coding exon 5) of the SEPT4 gene. This alteration results from a G to T substitution at nucleotide position 619, causing the valine (V) at amino acid position 207 to be replaced by a leucine (L). 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	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.12	.;.;.;T;D;.;T;.;.;T;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;.;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	N;.;D;.;N;.;.;N;N;.;.;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;.;D;.;D;.;.;D;D;.;.;.
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.20	B;B;P;.;B;B;.;B;B;.;.;.
Vest4		0.86
MutPred		0.79		.;.;.;.;Gain of sheet (P = 0.1451);.;.;.;.;.;.;.;
MVP		0.77
MPC		0.60
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.80
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1234386380; hg19: chr17-56602482;