11-27658057-C-T

Variant names:

• chr11-27658057-C-T
• rs77787410
• NM_001709.5:c.508G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001709.5(BDNF):​c.508G>A​(p.Val170Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BDNF NM_001709.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.17

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)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2743793).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDNF	NM_001709.5	c.508G>A	p.Val170Ile	missense_variant	Exon 2 of 2	ENST00000356660.9	NP_001700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BDNF	ENST00000356660.9	c.508G>A	p.Val170Ile	missense_variant	Exon 2 of 2	1	NM_001709.5	ENSP00000349084.4
BDNF	ENST00000533131.5	c.508G>A	p.Val170Ile	missense_variant	Exon 2 of 2	1		ENSP00000432727.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

BDNF-related disorder Uncertain:1

Apr 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BDNF c.754G>A variant is predicted to result in the amino acid substitution p.Val252Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. 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	Benign	0.12
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.28	T;T;.;T;T;T;T;T;T;.;T;T;T;T;T;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	.;.;D;.;.;.;.;.;.;D;D;.;.;.;.;.;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.92	L;L;.;L;L;L;L;L;L;.;L;L;L;L;L;L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.46	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.16	B;B;B;B;B;B;B;B;B;D;B;B;B;B;B;B;B
Vest4		0.44
MutPred		0.73		Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);.;Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);.;Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);Loss of methylation at K169 (P = 0.0778);.;
MVP		0.53
MPC		1.2
ClinPred		0.28	T
GERP RS		6.1
Varity_R		0.75
gMVP		0.56

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: rs77787410; hg19: chr11-27679604;