NM_002688.6:c.35C>T

Variant names:

• chr22-19714623-C-T
• rs1432426676
• NM_002688.6:c.35C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002688.6(SEPTIN5):​c.35C>T​(p.Ala12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000398 in 1,505,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A12A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SEPTIN5 NM_002688.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.756
• Publications: 1 publications found

Genes affected

SEPTIN5 (HGNC:9164): (septin 5) This gene is a member of the septin gene 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 mapped to 22q11, the region frequently deleted in DiGeorge and velocardiofacial syndromes. A translocation involving the MLL gene and this gene has also been reported in patients with acute myeloid leukemia. Alternative splicing results in multiple transcript variants. The presence of a non-consensus polyA signal (AACAAT) in this gene also results in read-through transcription into the downstream neighboring gene (GP1BB; platelet glycoprotein Ib), whereby larger, non-coding transcripts are produced. [provided by RefSeq, Dec 2010]

ENSG00000304096 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13275656).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002688.6. 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
	SEPTIN5	NM_002688.6	MANE Select	c.35C>T	p.Ala12Val	missense	Exon 1 of 12	NP_002679.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN5	ENST00000455784.7	TSL:1 MANE Select	c.35C>T	p.Ala12Val	missense	Exon 1 of 12	ENSP00000391311.2	Q99719-1
	SEPTIN5	ENST00000942371.1		c.35C>T	p.Ala12Val	missense	Exon 1 of 12	ENSP00000612430.1
	SEPTIN5	ENST00000406395.5	TSL:5	c.35C>T	p.Ala12Val	missense	Exon 1 of 12	ENSP00000384535.1	E7EX32

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149844 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000295 AC: 4 AN: 1355710 Hom.: 0 Cov.: 33 AF XY: 0.00000299 AC XY: 2 AN XY: 669030

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27634

American (AMR) AF: 0.00 AC: 0 AN: 33006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23940

East Asian (EAS) AF: 0.0000307 AC: 1 AN: 32546

South Asian (SAS) AF: 0.00 AC: 0 AN: 76516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4220

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1065654

Other (OTH) AF: 0.00 AC: 0 AN: 56314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000164189), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 149956 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73266

African (AFR) AF: 0.00 AC: 0 AN: 40970

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5022

South Asian (SAS) AF: 0.00 AC: 0 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67050

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

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	0.078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.76
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.030
Sift	Benign	0.31	T
Sift4G	Benign	0.29	T
Polyphen		0.0070	B
Vest4		0.20
MutPred		0.24		Loss of helix (P = 0.0376)
MVP		0.36
MPC		1.0
ClinPred		0.16	T
GERP RS		0.86
PromoterAI		-0.057	Neutral
Varity_R		0.060
gMVP		0.48
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1432426676; hg19: chr22-19702146;