NM_145799.4:c.271A>T

Variant names:

• chrX-119663552-T-A
• rs1000835123
• NM_145799.4:c.271A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_145799.4(SEPTIN6):​c.271A>T​(p.Ser91Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,095,299 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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. S91N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000064 (0 hom. 6 hem.)
  • Failed GnomAD Quality Control
• Consequence: SEPTIN6 NM_145799.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 6 gene

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.271A>T	p.Ser91Cys	missense	Exon 3 of 11	NP_665798.1	Q14141-2
	SEPTIN6	NM_015129.6		c.271A>T	p.Ser91Cys	missense	Exon 3 of 10	NP_055944.2
	SEPTIN6	NM_001410710.1		c.271A>T	p.Ser91Cys	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.271A>T	p.Ser91Cys	missense	Exon 3 of 11	ENSP00000378108.1	Q14141-2
	SEPTIN6	ENST00000343984.5	TSL:1	c.271A>T	p.Ser91Cys	missense	Exon 3 of 10	ENSP00000341524.5	Q14141-1
	SEPTIN6	ENST00000354228.8	TSL:1	c.271A>T	p.Ser91Cys	missense	Exon 3 of 10	ENSP00000346169.4	Q14141-4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 108433 Hom.: 0 Cov.: 21

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180707 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000639 AC: 7 AN: 1095299 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 6 AN XY: 360869

⚠️ 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: 26322

American (AMR) AF: 0.00 AC: 0 AN: 34970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19337

East Asian (EAS) AF: 0.00 AC: 0 AN: 30053

South Asian (SAS) AF: 0.000131 AC: 7 AN: 53569

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840533

Other (OTH) AF: 0.00 AC: 0 AN: 45964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 108433 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31037

African (AFR) AF: 0.00 AC: 0 AN: 29756

American (AMR) AF: 0.00 AC: 0 AN: 10120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2613

East Asian (EAS) AF: 0.00 AC: 0 AN: 3423

South Asian (SAS) AF: 0.00 AC: 0 AN: 2356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52250

Other (OTH) AF: 0.00 AC: 0 AN: 1461

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

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	0.13
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.65
MVP		0.62
MPC		1.6
ClinPred		0.88	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.57
Mutation Taster		=59/41	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: rs1000835123; hg19: chrX-118797515;