NM_000709.4:c.34C>A

Variant names:

• chr19-41397861-C-A
• rs34541442
• NM_000709.4:c.34C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000709.4(BCKDHA):​c.34C>A​(p.Arg12Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,172 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (9 hom., cov: 32)
  • Exomes 𝑓: 0.013 (156 hom.)
• Consequence: BCKDHA NM_000709.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0490
• Publications: 5 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, ClinGen, Myriad Women’s Health
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-41397861-C-A is Benign according to our data. Variant chr19-41397861-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.049 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0088 (1340/152340) while in subpopulation NFE AF = 0.0146 (993/68034). AF 95% confidence interval is 0.0138. There are 9 homozygotes in GnomAd4. There are 598 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000709.4. 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
	BCKDHA	NM_000709.4	MANE Select	c.34C>A	p.Arg12Arg	synonymous	Exon 1 of 9	NP_000700.1	P12694-1
	BCKDHA	NM_001164783.2		c.34C>A	p.Arg12Arg	synonymous	Exon 1 of 9	NP_001158255.1	Q59EI3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.34C>A	p.Arg12Arg	synonymous	Exon 1 of 9	ENSP00000269980.2	P12694-1
	ENSG00000255730	ENST00000540732.3	TSL:2	c.211-12776C>A		intron	N/A	ENSP00000443246.1	F5H5P2
	BCKDHA	ENST00000919033.1		c.34C>A	p.Arg12Arg	synonymous	Exon 1 of 10	ENSP00000589092.1

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152222 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0102 AC: 2560 AN: 250990 AF XY: 0.0104

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.00832

GnomAD4 exome AF: 0.0126 AC: 18478 AN: 1461832 Hom.: 156 Cov.: 32 AF XY: 0.0126 AC XY: 9141 AN XY: 727210

African (AFR) AF: 0.00188 AC: 63 AN: 33478

American (AMR) AF: 0.00575 AC: 257 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 416 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00859 AC: 741 AN: 86252

European-Finnish (FIN) AF: 0.00307 AC: 164 AN: 53400

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5766

European-Non Finnish (NFE) AF: 0.0145 AC: 16079 AN: 1111986

Other (OTH) AF: 0.0108 AC: 651 AN: 60392

GnomAD4 genome AF: 0.00880 AC: 1340 AN: 152340 Hom.: 9 Cov.: 32 AF XY: 0.00803 AC XY: 598 AN XY: 74486

African (AFR) AF: 0.00238 AC: 99 AN: 41598

American (AMR) AF: 0.00707 AC: 108 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 993 AN: 68034

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.0127 Hom.: 11

Bravo AF: 0.00875

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0143

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Maple syrup urine disease (3)
-	-	2	not provided (2)
-	-	1	Maple syrup urine disease type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.73
PhyloP100		0.049
PromoterAI		-0.072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs34541442; hg19: chr19-41903766;