22-41981711-C-T

Variant names:

• chr22-41981711-C-T
• rs140094386
• NM_001363845.2:c.1571C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001363845.2(SEPTIN3):​c.1571C>T​(p.Ala524Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,960 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: SEPTIN3 NM_001363845.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.36

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]

ENSG00000224883 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051607788).
• BP6: Variant 22-41981711-C-T is Benign according to our data. Variant chr22-41981711-C-T is described in ClinVar as [Benign]. Clinvar id is 738661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000834 (127/152296) while in subpopulation SAS AF = 0.022 (106/4824). AF 95% confidence interval is 0.0186. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEPTIN3	NM_001363845.2	c.1571C>T	p.Ala524Val	missense_variant	Exon 3 of 12	ENST00000644076.2	NP_001350774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEPTIN3	ENST00000644076.2	c.1571C>T	p.Ala524Val	missense_variant	Exon 3 of 12		NM_001363845.2	ENSP00000494051.1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00217 AC: 545 AN: 250838 AF XY: 0.00311

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00108 AC: 1574 AN: 1461664 Hom.: 24 Cov.: 31 AF XY: 0.00157 AC XY: 1145 AN XY: 727116

Gnomad4 AFR exome AF: 0.000418 AC: 14 AN: 33476

Gnomad4 AMR exome AF: 0.000157 AC: 7 AN: 44712

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26126

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39694

Gnomad4 SAS exome AF: 0.0168 AC: 1448 AN: 86224

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53360

Gnomad4 NFE exome AF: 0.0000423 AC: 47 AN: 1111942

Gnomad4 Remaining exome AF: 0.000894 AC: 54 AN: 60386

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74476

Gnomad4 AFR AF: 0.000241 AC: 0.000240604 AN: 0.000240604

Gnomad4 AMR AF: 0.000261 AC: 0.000261472 AN: 0.000261472

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.0220 AC: 0.0219735 AN: 0.0219735

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000882 AC: 0.0000882068 AN: 0.0000882068

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 02, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	.;T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;T;T;T
MetaRNN	Benign	0.0052	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;.;L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	.;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.20	.;T;T;T
Sift4G	Benign	0.20	.;T;T;T
Polyphen		0.0010, 0.0	.;.;B;B
Vest4		0.20, 0.20
MVP		0.69
MPC		0.81
ClinPred		0.018	T
GERP RS		5.6
Varity_R		0.076
gMVP		0.30
Mutation Taster		=98/2	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

Publications

LitVar

Other links and lift over

dbSNP: rs140094386; hg19: chr22-42377715;