11-27658560-G-T

Position:

chr11-27658560-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001709.5(BDNF):c.5C>A(p.Thr2Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

BDNF
NM_001709.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00

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 links:

BDNF-AS (HGNC:20608): (BDNF antisense RNA)

BDNF-AS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BDNF	NM_001709.5 linkuse as main transcript	c.5C>A	p.Thr2Asn	missense_variant	2/2	ENST00000356660.9
BDNF-AS	NR_033312.1 linkuse as main transcript	n.527+98G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BDNF	ENST00000356660.9 linkuse as main transcript	c.5C>A	p.Thr2Asn	missense_variant	2/2	1	NM_001709.5	P4	P23560-1
BDNF-AS	ENST00000651238.1 linkuse as main transcript	n.601+98G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

250832

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000247

AC:

361

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

190

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000272

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

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 submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2023

The BDNF c.251C>A variant is predicted to result in the amino acid substitution p.Thr84Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-27680107-G-T), which is higher than expected for a pathogenic variant in this gene. An alternate change at the same amino acid position was initially documented in association with central hypoventilation syndrome (p.Thr84Ile, documented in the literature on an alternate transcript – NM_001709.5 p.Thr2Ile; Weese-Mayer et al. 2002. PubMed ID: 11840487; Friedel et al. 2005. PubMed ID: 15457498). However, it has an even higher allele frequency than the p.Thr84Asn change, and its pathogenicity was called into question by multiple later reports (Abouelhoda et al. 2016. PubMed ID: 27884173; Rego et al. 2018. PubMed ID: 30487145). Although we suspect that the c.251C>A (p.Thr84Asn) variant may be benign, 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

0.40

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.37

T;T;.;T;T;T;T;T;T;.;T;T;T;T;T;T;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.57

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.9

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

0.83

PROVEAN

Benign

-0.23

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.26

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.14

T;T;D;T;T;T;T;T;T;D;T;T;T;T;T;T;D

Polyphen

0.95

P;P;D;P;P;P;P;P;P;D;P;P;P;P;P;P;D

Vest4

0.76

MVP

0.69

MPC

1.6

ClinPred

0.12

GERP RS

6.0

Varity_R

0.43

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over