rs148571328

Variant names:

• chr19-41410816-C-G
• rs148571328
• NM_000709.4:c.288C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-41410816-C-G
• chr19-41410816-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000709.4(BCKDHA):​c.288C>G​(p.His96Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 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. Synonymous variant affecting the same amino acid position (i.e. H96H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BCKDHA NM_000709.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004479
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.994
• Publications: 0 publications found

Genes affected

BCKDHA (HGNC:986): (branched chain keto acid dehydrogenase E1 subunit alpha) The branched-chain alpha-keto acid (BCAA) dehydrogenase (BCKD) complex is an innter mitochondrial enzyme complex that catalyzes the second major step in the catabolism of the branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex consists of three catalytic components: a heterotetrameric (alpha2-beta2) branched-chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). This gene encodes the alpha subunit of the decarboxylase (E1) component. Mutations in this gene result in maple syrup urine disease, type IA. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

BCKDHA Gene-Disease associations (from GenCC):

• maple syrup urine disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• maple syrup urine disease type 1A

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women’s Health, ClinGen
• classic maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermittent maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thiamine-responsive maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255730 (HGNC:):

ACMG classification

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=0.076884925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4	c.288C>G	p.His96Gln	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.288C>G	p.His96Gln	missense_variant, splice_region_variant	Exon 2 of 9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.288C>G	p.His96Gln	missense_variant, splice_region_variant	Exon 2 of 9	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.390C>G	p.His130Gln	missense_variant, splice_region_variant	Exon 3 of 10	2		ENSP00000443246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727236

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 53394

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.0010
DANN	Benign	0.67
DEOGEN2	Benign	0.0	.;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.72	T;T;T;T
MetaRNN	Benign	0.032	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N;.;.
PhyloP100		-0.99
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.19	N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.83	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Vest4		0.16
ClinPred		0.046	T
GERP RS		-11
PromoterAI		0.028	Neutral
Varity_R		0.12
gMVP		0.27
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.14
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: rs148571328; hg19: chr19-41916721;