X-119663525-C-G

Variant names:

• chrX-119663525-C-G
• rs138699101
• NM_145799.4:c.298G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145799.4(SEPTIN6):​c.298G>C​(p.Val100Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000109 in 919,257 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V100I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 hem.)
• Consequence: SEPTIN6 NM_145799.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56
• Publications: 0 publications found

Genes affected

SEPTIN6 (HGNC:15848): (septin 6) This gene is a member of the septin family of GTPases. Members of this family are required for cytokinesis. One version of pediatric acute myeloid leukemia is the result of a reciprocal translocation between chromosomes 11 and X, with the breakpoint associated with the genes encoding the mixed-lineage leukemia and septin 2 proteins. This gene encodes four transcript variants encoding three distinct isoforms. An additional transcript variant has been identified, but its biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145799.4. 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
	SEPTIN6	NM_145799.4	MANE Select	c.298G>C	p.Val100Leu	missense	Exon 3 of 11	NP_665798.1	Q14141-2
	SEPTIN6	NM_015129.6		c.298G>C	p.Val100Leu	missense	Exon 3 of 10	NP_055944.2
	SEPTIN6	NM_001410710.1		c.298G>C	p.Val100Leu	missense	Exon 3 of 10	NP_001397639.1	B1AMS2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN6	ENST00000394610.7	TSL:1 MANE Select	c.298G>C	p.Val100Leu	missense	Exon 3 of 11	ENSP00000378108.1	Q14141-2
	SEPTIN6	ENST00000343984.5	TSL:1	c.298G>C	p.Val100Leu	missense	Exon 3 of 10	ENSP00000341524.5	Q14141-1
	SEPTIN6	ENST00000354228.8	TSL:1	c.298G>C	p.Val100Leu	missense	Exon 3 of 10	ENSP00000346169.4	Q14141-4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000109 AC: 1 AN: 919257 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 301837

African (AFR) AF: 0.00 AC: 0 AN: 20930

American (AMR) AF: 0.00 AC: 0 AN: 29395

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12891

East Asian (EAS) AF: 0.00 AC: 0 AN: 13585

South Asian (SAS) AF: 0.00 AC: 0 AN: 51478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3252

European-Non Finnish (NFE) AF: 0.00000137 AC: 1 AN: 728464

Other (OTH) AF: 0.00 AC: 0 AN: 33924

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.022	D
Polyphen		0.076	B
Vest4		0.87
MVP		0.68
MPC		0.93
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.71
gMVP		0.74
Mutation Taster		=70/30	polymorphism

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: rs138699101; hg19: chrX-118797488;