16-4783969-C-T

Variant names:

• chr16-4783969-C-T
• rs759991
• NM_144605.5:c.474G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_144605.5(SEPTIN12):​c.474G>A​(p.Val158Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,613,832 control chromosomes in the GnomAD database, including 62,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5019 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57084 hom.)
• Consequence: SEPTIN12 NM_144605.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.0850
• Publications: 30 publications found

Genes affected

SEPTIN12 (HGNC:26348): (septin 12) This gene encodes a guanine-nucleotide binding protein and member of the septin family of cytoskeletal GTPases. Septins play important roles in cytokinesis, exocytosis, embryonic development, and membrane dynamics. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

SEPTIN12 Gene-Disease associations (from GenCC):

• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 10

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000285952 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 16-4783969-C-T is Benign according to our data. Variant chr16-4783969-C-T is described in ClinVar as Benign. ClinVar VariationId is 37113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144605.5. 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
	SEPTIN12	NM_144605.5	MANE Select	c.474G>A	p.Val158Val	synonymous	Exon 5 of 10	NP_653206.2
	SEPTIN12	NM_001154458.3		c.375-203G>A		intron	N/A	NP_001147930.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN12	ENST00000268231.13	TSL:1 MANE Select	c.474G>A	p.Val158Val	synonymous	Exon 5 of 10	ENSP00000268231.8
	SEPTIN12	ENST00000396693.9	TSL:1	c.375-203G>A		intron	N/A	ENSP00000379922.4
	SEPTIN12	ENST00000587603.5	TSL:2	n.474G>A		non_coding_transcript_exon	Exon 5 of 10	ENSP00000467237.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38077 AN: 152036 Hom.: 4997 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.272

GnomAD2 exomes AF: 0.290 AC: 72791 AN: 251296 AF XY: 0.294

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.305

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.275 AC: 401912 AN: 1461678 Hom.: 57084 Cov.: 37 AF XY: 0.279 AC XY: 202872 AN XY: 727160

African (AFR) AF: 0.193 AC: 6469 AN: 33476

American (AMR) AF: 0.330 AC: 14774 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 8977 AN: 26132

East Asian (EAS) AF: 0.327 AC: 12972 AN: 39700

South Asian (SAS) AF: 0.405 AC: 34906 AN: 86254

European-Finnish (FIN) AF: 0.193 AC: 10302 AN: 53418

Middle Eastern (MID) AF: 0.295 AC: 1702 AN: 5768

European-Non Finnish (NFE) AF: 0.265 AC: 294463 AN: 1111824

Other (OTH) AF: 0.287 AC: 17347 AN: 60382

GnomAD4 genome AF: 0.251 AC: 38140 AN: 152154 Hom.: 5019 Cov.: 32 AF XY: 0.250 AC XY: 18605 AN XY: 74368

African (AFR) AF: 0.199 AC: 8266 AN: 41534

American (AMR) AF: 0.281 AC: 4293 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1187 AN: 3468

East Asian (EAS) AF: 0.317 AC: 1635 AN: 5160

South Asian (SAS) AF: 0.412 AC: 1978 AN: 4806

European-Finnish (FIN) AF: 0.171 AC: 1817 AN: 10612

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18155 AN: 67978

Other (OTH) AF: 0.274 AC: 578 AN: 2112

Alfa AF: 0.266 Hom.: 11894

Bravo AF: 0.255

Asia WGS AF: 0.406 AC: 1409 AN: 3478

EpiCase AF: 0.273

EpiControl AF: 0.285

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	Spermatogenic failure 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.3
DANN	Benign	0.53
PhyloP100		0.085
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.71		Position offset: 3
DS_DL_spliceai		0.34		Position offset: -38

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759991; hg19: chr16-4833970; COSMIC: COSV51615609; COSMIC: COSV51615609;