rs34762726

chr3-49651777-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_003458.4(BSN):c.2221G>A(p.Ala741Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,612,844 control chromosomes in the GnomAD database, including 69,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.28 (6416 hom., cov: 32)
  • Exomes 𝑓: 0.28 (62635 hom.)
• Consequence: BSN NM_003458.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.52

Genes affected

BSN (HGNC:1117): (bassoon presynaptic cytomatrix protein) Neurotransmitters are released from a specific site in the axon terminal called the active zone, which is composed of synaptic vesicles and a meshwork of cytoskeleton underlying the plasma membrane. The protein encoded by this gene is thought to be a scaffolding protein involved in organizing the presynaptic cytoskeleton. The gene is expressed primarily in neurons in the brain. A similar gene product in rodents is concentrated in the active zone of axon terminals and tightly associated with cytoskeletal structures, and is essential for regulating neurotransmitter release from a subset of synapses. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BSN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027731955).
• BP6: Variant 3-49651777-G-A is Benign according to our data. Variant chr3-49651777-G-A is described in ClinVar as [Benign]. Clinvar id is 3057088.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BSN	NM_003458.4	c.2221G>A	p.Ala741Thr	missense_variant	5/12	ENST00000296452.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BSN	ENST00000296452.5	c.2221G>A	p.Ala741Thr	missense_variant	5/12	1	NM_003458.4	P1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42478 AN: 151924 Hom.: 6412 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.0459

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.266 AC: 66161 AN: 248622 Hom.: 10282 AF XY: 0.269 AC XY: 36232 AN XY: 134734

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.441

Gnomad EAS exome AF: 0.0451

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.443

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.284 AC: 415597 AN: 1460802 Hom.: 62635 Cov.: 45 AF XY: 0.283 AC XY: 205944 AN XY: 726714

Gnomad4 AFR exome AF: 0.273

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.440

Gnomad4 EAS exome AF: 0.0436

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.431

Gnomad4 NFE exome AF: 0.292

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.280 AC: 42507 AN: 152042 Hom.: 6416 Cov.: 32 AF XY: 0.282 AC XY: 20926 AN XY: 74328

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.443

Gnomad4 EAS AF: 0.0460

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.447

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.284

Alfa AF: 0.285 Hom.: 10251

Bravo AF: 0.262

TwinsUK AF: 0.300 AC: 1114

ALSPAC AF: 0.285 AC: 1097

ESP6500AA AF: 0.268 AC: 1179

ESP6500EA AF: 0.298 AC: 2566

ExAC AF: 0.263 AC: 31954

Asia WGS AF: 0.135 AC: 475 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BSN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	16
Dann	Benign	0.65
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.072
Sift	Benign	0.88	T
Sift4G	Benign	0.51	T
Polyphen		0.0030	B
Vest4		0.062
MPC		0.27
ClinPred		0.0076	T
GERP RS		4.2
Varity_R		0.033
gMVP		0.10

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: rs34762726; hg19: chr3-49689210;