X-119663551-C-T

Variant names:

• chrX-119663551-C-T
• rs1243232786
• NM_145799.4:c.272G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145799.4(SEPTIN6):​c.272G>A​(p.Ser91Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000928 in 1,077,548 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S91C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.3e-7 (0 hom. 1 hem.)
• Consequence: SEPTIN6 NM_145799.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN6	NM_145799.4	c.272G>A	p.Ser91Asn	missense_variant	Exon 3 of 11	ENST00000394610.7	NP_665798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN6	ENST00000394610.7	c.272G>A	p.Ser91Asn	missense_variant	Exon 3 of 11	1	NM_145799.4	ENSP00000378108.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000553 AC: 1 AN: 180749 Hom.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65437

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 9.28e-7 AC: 1 AN: 1077548 Hom.: 0 Cov.: 32 AF XY: 0.00000285 AC XY: 1 AN XY: 350846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000534

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.272G>A (p.S91N) alteration is located in exon 3 (coding exon 3) of the SEPT6 gene. This alteration results from a G to A substitution at nucleotide position 272, causing the serine (S) at amino acid position 91 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	.;.;.;T;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.2	L;L;L;.;L;L
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.23	T;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T
Polyphen		0.78	.;.;.;.;.;P
Vest4		0.56
MVP		0.32
MPC		1.2
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.66
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs1243232786; hg19: chrX-118797514;