rs4674

Variant names:

• chr19-41424491-A-G
• rs4674
• NM_000709.4:c.1221A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000709.4(BCKDHA):​c.1221A>G​(p.Leu407Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,613,672 control chromosomes in the GnomAD database, including 305,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L407L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.66 (33918 hom., cov: 31)
  • Exomes 𝑓: 0.61 (271438 hom.)
• Consequence: BCKDHA NM_000709.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.759
• Publications: 44 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-41424491-A-G is Benign according to our data. Variant chr19-41424491-A-G is described in ClinVar as Benign. ClinVar VariationId is 93343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.759 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

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.1221A>G	p.Leu407Leu	synonymous	Exon 9 of 9	NP_000700.1
	BCKDHA	NM_001164783.2		c.1218A>G	p.Leu406Leu	synonymous	Exon 9 of 9	NP_001158255.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.1221A>G	p.Leu407Leu	synonymous	Exon 9 of 9	ENSP00000269980.2
	ENSG00000255730	ENST00000540732.3	TSL:2	c.1323A>G	p.Leu441Leu	synonymous	Exon 10 of 10	ENSP00000443246.1
	BCKDHA	ENST00000919033.1		c.1449A>G	p.Leu483Leu	synonymous	Exon 10 of 10	ENSP00000589092.1

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99862 AN: 151750 Hom.: 33876 Cov.: 31

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.639

GnomAD2 exomes AF: 0.592 AC: 147600 AN: 249152 AF XY: 0.592

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.626

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.656

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.607 AC: 886891 AN: 1461804 Hom.: 271438 Cov.: 70 AF XY: 0.606 AC XY: 440439 AN XY: 727208

African (AFR) AF: 0.833 AC: 27873 AN: 33480

American (AMR) AF: 0.485 AC: 21706 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 16340 AN: 26134

East Asian (EAS) AF: 0.465 AC: 18449 AN: 39698

South Asian (SAS) AF: 0.583 AC: 50314 AN: 86258

European-Finnish (FIN) AF: 0.655 AC: 34970 AN: 53388

Middle Eastern (MID) AF: 0.637 AC: 3673 AN: 5768

European-Non Finnish (NFE) AF: 0.608 AC: 676435 AN: 1111970

Other (OTH) AF: 0.615 AC: 37131 AN: 60390

GnomAD4 genome AF: 0.658 AC: 99957 AN: 151868 Hom.: 33918 Cov.: 31 AF XY: 0.655 AC XY: 48630 AN XY: 74198

African (AFR) AF: 0.822 AC: 34072 AN: 41462

American (AMR) AF: 0.561 AC: 8563 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2177 AN: 3470

East Asian (EAS) AF: 0.438 AC: 2251 AN: 5140

South Asian (SAS) AF: 0.588 AC: 2823 AN: 4804

European-Finnish (FIN) AF: 0.663 AC: 6991 AN: 10552

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.602 AC: 40846 AN: 67860

Other (OTH) AF: 0.639 AC: 1346 AN: 2106

Alfa AF: 0.620 Hom.: 54849

Bravo AF: 0.658

Asia WGS AF: 0.538 AC: 1869 AN: 3478

EpiCase AF: 0.598

EpiControl AF: 0.604

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Maple syrup urine disease (4)
-	-	4	not specified (4)
-	-	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	-0.66
CADD	Benign	8.0
DANN	Benign	0.79
PhyloP100		0.76
Mutation Taster		=99/1	polymorphism (auto)

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: rs4674; hg19: chr19-41930396; COSMIC: COSV54195656; COSMIC: COSV54195656;