12-24832725-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005504.7(BCAT1):c.1042G>C(p.Glu348Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. E348K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BCAT1
NM_005504.7 missense, splice_region

Scores

Splicing: ADA: 0.00007186

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.385

Publications

0 publications found

Variant links:

Genes affected

BCAT1 (HGNC:976): (branched chain amino acid transaminase 1) This gene encodes the cytosolic form of the enzyme branched-chain amino acid transaminase. This enzyme catalyzes the reversible transamination of branched-chain alpha-keto acids to branched-chain L-amino acids essential for cell growth. Two different clinical disorders have been attributed to a defect of branched-chain amino acid transamination: hypervalinemia and hyperleucine-isoleucinemia. As there is also a gene encoding a mitochondrial form of this enzyme, mutations in either gene may contribute to these disorders. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2010]

BCAT1 links:

BCAT1-AS1 (HGNC:58192):

BCAT1-AS1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0419209).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005504.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BCAT1	NM_005504.7	MANE Select	c.1042G>C	p.Glu348Gln	missense splice_region	Exon 9 of 11	NP_005495.2
BCAT1	NM_001413086.1		c.1078G>C	p.Glu360Gln	missense splice_region	Exon 9 of 12	NP_001400015.1
BCAT1	NM_001413087.1		c.1114G>C	p.Glu372Gln	missense splice_region	Exon 9 of 11	NP_001400016.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCAT1	ENST00000261192.12	TSL:1 MANE Select	c.1042G>C	p.Glu348Gln	missense splice_region	Exon 9 of 11	ENSP00000261192.7	P54687-1
BCAT1	ENST00000538118.5	TSL:1	c.1039G>C	p.Glu347Gln	missense splice_region	Exon 9 of 11	ENSP00000440817.1	P54687-4
BCAT1	ENST00000539282.5	TSL:2	c.1078G>C	p.Glu360Gln	missense splice_region	Exon 9 of 11	ENSP00000443459.1	P54687-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450888

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720998

show subpopulations

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

African (AFR)

AF:

0.0000302

AC:

AN:

33154

American (AMR)

AF:

0.00

AC:

AN:

42730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25712

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.00

AC:

AN:

83818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107184

Other (OTH)

AF:

0.00

AC:

AN:

59936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.23

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.81

M_CAP

Benign

0.0058

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.74

PhyloP100

0.39

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.23

REVEL

Benign

0.065

Sift

Benign

0.63

Sift4G

Benign

0.52

Polyphen

0.013

Vest4

0.055

MutPred

0.38

Gain of methylation at K346 (P = 0.1019)

MVP

0.22

MPC

0.023

ClinPred

0.20

GERP RS

0.40

Varity_R

0.23

gMVP

0.69

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000072

dbscSNV1_RF

Benign

0.024

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

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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