11-27657844-A-T

Variant names:

• chr11-27657844-A-T
• rs1852776284
• NM_001709.5:c.721T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001709.5(BDNF):​c.721T>A​(p.Leu241Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L241L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BDNF NM_001709.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.720
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001709.5. 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
	BDNF	NM_001709.5	MANE Select	c.721T>A	p.Leu241Met	missense	Exon 2 of 2	NP_001700.2
	BDNF	NM_001143810.2		c.967T>A	p.Leu323Met	missense	Exon 3 of 3	NP_001137282.1	P23560-4
	BDNF	NM_001143809.2		c.808T>A	p.Leu270Met	missense	Exon 2 of 2	NP_001137281.1	P23560-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BDNF	ENST00000356660.9	TSL:1 MANE Select	c.721T>A	p.Leu241Met	missense	Exon 2 of 2	ENSP00000349084.4	P23560-1
	BDNF	ENST00000438929.5	TSL:1	c.967T>A	p.Leu323Met	missense	Exon 3 of 3	ENSP00000414303.1	P23560-4
	BDNF	ENST00000395986.6	TSL:1	c.766T>A	p.Leu256Met	missense	Exon 2 of 2	ENSP00000379309.2	P23560-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.16
Eigen_PC	Benign	-0.0027
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.72
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.80		Gain of methylation at K244 (P = 0.0667)
MVP		0.82
MPC		1.5
ClinPred		0.98	D
GERP RS		-5.1
Varity_R		0.86
gMVP		0.71
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs1852776284; hg19: chr11-27679391;