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GeneBe

11-27657906-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001709.5(BDNF):c.659T>C(p.Met220Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

BDNF
NM_001709.5 missense

Scores

5
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51
Variant links:
Genes affected
BDNF (HGNC:1033): (brain derived neurotrophic factor) This gene encodes a member of the nerve growth factor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protein. Binding of this protein to its cognate receptor promotes neuronal survival in the adult brain. Expression of this gene is reduced in Alzheimer's, Parkinson's, and Huntington's disease patients. This gene may play a role in the regulation of the stress response and in the biology of mood disorders. [provided by RefSeq, Nov 2015]
BDNF-AS (HGNC:20608): (BDNF antisense RNA)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BDNFNM_001709.5 linkuse as main transcriptc.659T>C p.Met220Thr missense_variant 2/2 ENST00000356660.9
BDNF-ASNR_033312.1 linkuse as main transcriptn.306-335A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BDNFENST00000356660.9 linkuse as main transcriptc.659T>C p.Met220Thr missense_variant 2/21 NM_001709.5 P4P23560-1
BDNF-ASENST00000651238.1 linkuse as main transcriptn.380-335A>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

BDNF-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 26, 2023The BDNF c.905T>C variant is predicted to result in the amino acid substitution p.Met302Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
25
DANN
Benign
0.88
DEOGEN2
Uncertain
0.48
T;T;.;T;T;T;T;T;T;.;T;T;T;T;T;T;.
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Benign
0.061
D
MetaRNN
Pathogenic
0.82
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.52
T
MutationAssessor
Benign
1.4
L;L;.;L;L;L;L;L;L;.;L;L;L;L;L;L;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-2.3
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.52
Sift
Uncertain
0.011
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.37
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.23
B;B;B;B;B;B;B;B;B;P;B;B;B;B;B;B;B
Vest4
0.80
MutPred
0.67
Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);.;Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);.;Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);Gain of phosphorylation at M220 (P = 0.0288);.;
MVP
0.88
MPC
1.4
ClinPred
0.89
D
GERP RS
6.1
Varity_R
0.61
gMVP
0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-27679453; API