3-49651777-G-A

Variant names:

• chr3-49651777-G-A
• rs34762726
• NM_003458.4:c.2221G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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 no assertion criteria provided 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

Our verdict: Benign. The variant received -13 ACMG points.

• 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 no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
BSN	NM_003458.4	c.2221G>A	p.Ala741Thr	missense_variant	Exon 5 of 12	ENST00000296452.5	NP_003449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BSN	ENST00000296452.5	c.2221G>A	p.Ala741Thr	missense_variant	Exon 5 of 12	1	NM_003458.4	ENSP00000296452.4

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

GnomAD2 exomes AF: 0.266 AC: 66161 AN: 248622 AF XY: 0.269

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 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 AC: 9130 AN: 33476

Gnomad4 AMR exome AF: 0.158 AC: 7051 AN: 44692

Gnomad4 ASJ exome AF: 0.440 AC: 11506 AN: 26124

Gnomad4 EAS exome AF: 0.0436 AC: 1729 AN: 39696

Gnomad4 SAS exome AF: 0.234 AC: 20162 AN: 86236

Gnomad4 FIN exome AF: 0.431 AC: 22707 AN: 52648

Gnomad4 NFE exome AF: 0.292 AC: 324190 AN: 1111918

Gnomad4 Remaining exome AF: 0.288 AC: 17404 AN: 60362

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 AC: 0.271528 AN: 0.271528

Gnomad4 AMR AF: 0.207 AC: 0.206933 AN: 0.206933

Gnomad4 ASJ AF: 0.443 AC: 0.442651 AN: 0.442651

Gnomad4 EAS AF: 0.0460 AC: 0.046017 AN: 0.046017

Gnomad4 SAS AF: 0.215 AC: 0.215385 AN: 0.215385

Gnomad4 FIN AF: 0.447 AC: 0.446682 AN: 0.446682

Gnomad4 NFE AF: 0.290 AC: 0.289622 AN: 0.289622

Gnomad4 OTH AF: 0.284 AC: 0.284425 AN: 0.284425

Alfa AF: 0.283 Hom.: 14147

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: no assertion criteria provided

Submissions by phenotype

BSN-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
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
Mutation Taster		=92/8	polymorphism (auto)

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; COSMIC: COSV107364574; COSMIC: COSV107364574;