Genetic Variant BEGAIN:p.Ala471Thr (chr14-100538397-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001385089.1(BEGAIN):c.1411G>A(p.Ala471Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,389,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A471P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

BEGAIN
NM_001385089.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.02

Publications

0 publications found

Variant links:

Genes affected

BEGAIN (HGNC:24163): (brain enriched guanylate kinase associated) Predicted to be involved in regulation of postsynaptic neurotransmitter receptor activity. Predicted to act upstream of or within evoked excitatory postsynaptic potential. Predicted to be located in dendrite; nucleus; and presynapse. Predicted to be active in glutamatergic synapse and postsynapse. [provided by Alliance of Genome Resources, Apr 2022]

BEGAIN links:

LOC124903382 (HGNC:):

LOC124903382 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07346058).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385089.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BEGAIN	NM_001385089.1	MANE Select	c.1411G>A	p.Ala471Thr	missense	Exon 7 of 7	NP_001372018.1	G3V3A2
BEGAIN	NM_001385085.1		c.1501G>A	p.Ala501Thr	missense	Exon 8 of 8	NP_001372014.1
BEGAIN	NM_001385086.1		c.1483G>A	p.Ala495Thr	missense	Exon 8 of 8	NP_001372015.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BEGAIN	ENST00000554140.3	TSL:5 MANE Select	c.1411G>A	p.Ala471Thr	missense	Exon 7 of 7	ENSP00000451125.2	G3V3A2
BEGAIN	ENST00000355173.7	TSL:1	c.1354G>A	p.Ala452Thr	missense	Exon 7 of 7	ENSP00000347301.2	Q9BUH8
BEGAIN	ENST00000557378.6	TSL:1	c.1354G>A	p.Ala452Thr	missense	Exon 6 of 6	ENSP00000450722.2	Q9BUH8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000216

AC:

AN:

1389724

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

686382

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30210

American (AMR)

AF:

0.00

AC:

AN:

33764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21910

East Asian (EAS)

AF:

0.00

AC:

AN:

38226

South Asian (SAS)

AF:

0.00

AC:

AN:

76650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5502

European-Non Finnish (NFE)

AF:

0.00000277

AC:

AN:

1081462

Other (OTH)

AF:

0.00

AC:

AN:

57168

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00846340), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.8

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0098

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.74

M_CAP

Benign

0.010

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-1.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.67

REVEL

Benign

0.0070

Sift

Benign

0.092

Sift4G

Benign

0.20

Polyphen

0.020

Vest4

0.057

MutPred

0.23

Gain of catalytic residue at G453 (P = 3e-04)

MVP

0.17

MPC

0.43

ClinPred

0.052

GERP RS

-0.56

Varity_R

0.053

gMVP

0.12

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over