17-58520745-C-T

Variant names:

• chr17-58520745-C-T
• rs191011663
• NM_001368771.2:c.2929G>A
• SEPTIN4 p.Glu977Lys

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001368771.2(SEPTIN4):​c.2929G>A​(p.Glu977Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,614,134 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E977Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: SEPTIN4 NM_001368771.2 missense, splice_region
• Scores: Splicing: ADA: 0.2517
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.84
• Publications: 2 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009610981).
• BP6: Variant 17-58520745-C-T is Benign according to our data. Variant chr17-58520745-C-T is described in ClinVar as Benign. ClinVar VariationId is 778530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.2929G>A	p.Glu977Lys	missense splice_region	Exon 13 of 14	NP_001355700.1	O43236-7
	SEPTIN4	NM_001256782.2		c.1420G>A	p.Glu474Lys	missense splice_region	Exon 12 of 13	NP_001243711.1	O43236-4
	SEPTIN4	NM_004574.5		c.1375G>A	p.Glu459Lys	missense splice_region	Exon 11 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.2929G>A	p.Glu977Lys	missense splice_region	Exon 13 of 14	ENSP00000500383.1	O43236-7
	SEPTIN4	ENST00000317268.7	TSL:1	c.1375G>A	p.Glu459Lys	missense splice_region	Exon 11 of 12	ENSP00000321674.3	O43236-1
	SEPTIN4	ENST00000317256.10	TSL:1	c.1318G>A	p.Glu440Lys	missense splice_region	Exon 11 of 12	ENSP00000321071.6	O43236-2

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152180 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00219 AC: 551 AN: 251470 AF XY: 0.00148

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000482 AC: 704 AN: 1461836 Hom.: 6 Cov.: 30 AF XY: 0.000378 AC XY: 275 AN XY: 727220

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0148 AC: 664 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112012

Other (OTH) AF: 0.000480 AC: 29 AN: 60392

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152298 Hom.: 1 Cov.: 31 AF XY: 0.000631 AC XY: 47 AN XY: 74468

African (AFR) AF: 0.000193 AC: 8 AN: 41556

American (AMR) AF: 0.00542 AC: 83 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.00145

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.33
Sift	Benign	0.076	T
Sift4G	Benign	0.38	T
Varity_R		0.68
gMVP		0.84
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.25
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs191011663; hg19: chr17-56598106;