chr22-41992666-G-C

Variant names:

• chr22-41992666-G-C
• rs9611697
• NM_001363845.2:c.2262G>C

Variant summary

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

The NM_001363845.2(SEPTIN3):​c.2262G>C​(p.Gln754His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEPTIN3 NM_001363845.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.62
• Publications: 0 publications found

Genes affected

SEPTIN3 (HGNC:10750): (septin 3) This gene belongs to the septin family of GTPases. Members of this family are required for cytokinesis. Expression is upregulated by retinoic acid in a human teratocarcinoma cell line. The specific function of this gene has not been determined. Alternative splicing of this gene results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2018]

ENSG00000301540 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363845.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN3	NM_001363845.2	MANE Select	c.2262G>C	p.Gln754His	missense splice_region	Exon 9 of 12	NP_001350774.1
	SEPTIN3	NM_001389668.1		c.2262G>C	p.Gln754His	missense splice_region	Exon 9 of 11	NP_001376597.1
	SEPTIN3	NM_001389669.1		c.2133G>C	p.Gln711His	missense splice_region	Exon 8 of 11	NP_001376598.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN3	ENST00000644076.2	MANE Select	c.2262G>C	p.Gln754His	missense splice_region	Exon 9 of 12	ENSP00000494051.1
	SEPTIN3	ENST00000396426.7	TSL:1	c.768G>C	p.Gln256His	missense splice_region	Exon 8 of 11	ENSP00000379704.3
	SEPTIN3	ENST00000396425.8	TSL:1	c.768G>C	p.Gln256His	missense splice_region	Exon 8 of 10	ENSP00000379703.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.39
Sift	Benign	0.098	T
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.55		Gain of catalytic residue at I254 (P = 0.1039)
MVP		0.89
MPC		1.0
ClinPred		0.74	D
GERP RS		5.6
Varity_R		0.40
gMVP		0.64
Mutation Taster		=31/69	disease causing

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

dbSNP: rs9611697; hg19: chr22-42388670;