chr22-19720550-C-T

Variant names:

• chr22-19720550-C-T
• rs778796449
• NM_002688.6:c.499C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_002688.6(SEPTIN5):​c.499C>T​(p.Leu167Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SEPTIN5 NM_002688.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.001911
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.413
• Publications: 0 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]

ENSG00000284874 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 22-19720550-C-T is Benign according to our data. Variant chr22-19720550-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 760618.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.413 with no splicing effect.

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.499C>T	p.Leu167Leu	splice_region synonymous	Exon 7 of 12	NP_002679.2
	SEPTIN5	NM_001009939.3		c.526C>T	p.Leu176Leu	splice_region synonymous	Exon 6 of 11	NP_001009939.1	Q99719-2
	SEPT5-GP1BB	NR_037611.1		n.2044C>T		splice_region non_coding_transcript_exon	Exon 6 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN5	ENST00000455784.7	TSL:1 MANE Select	c.499C>T	p.Leu167Leu	splice_region synonymous	Exon 7 of 12	ENSP00000391311.2	Q99719-1
	ENSG00000284874	ENST00000431044.5	TSL:1	n.358C>T		splice_region non_coding_transcript_exon	Exon 6 of 12	ENSP00000399685.1	F6X4M4
	ENSG00000284874	ENST00000455843.5	TSL:1	n.526C>T		splice_region non_coding_transcript_exon	Exon 6 of 12	ENSP00000391731.1	G3XAH0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250224 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460818 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726704

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000895 AC: 4 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52402

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.41
PromoterAI		-0.0014	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.034
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

dbSNP: rs778796449; hg19: chr22-19708073;