19-41419289-C-T

Variant names:

• chr19-41419289-C-T
• rs10404506
• NM_000709.4:c.639C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_000709.4(BCKDHA):​c.639C>T​(p.Ile213Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,613,130 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I213I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (97 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (88 hom.)
• Consequence: BCKDHA NM_000709.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.02
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.275).
• BP6: Variant 19-41419289-C-T is Benign according to our data. Variant chr19-41419289-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0602 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.639C>T	p.Ile213Ile	synonymous	Exon 5 of 9	NP_000700.1	P12694-1
	BCKDHA	NM_001164783.2		c.639C>T	p.Ile213Ile	synonymous	Exon 5 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.639C>T	p.Ile213Ile	synonymous	Exon 5 of 9	ENSP00000269980.2	P12694-1
	ENSG00000255730	ENST00000540732.3	TSL:2	c.741C>T	p.Ile247Ile	synonymous	Exon 6 of 10	ENSP00000443246.1	F5H5P2
	BCKDHA	ENST00000919033.1		c.639C>T	p.Ile213Ile	synonymous	Exon 5 of 10	ENSP00000589092.1

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2719 AN: 152188 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00461 AC: 1148 AN: 248758 AF XY: 0.00341

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00192 AC: 2808 AN: 1460824 Hom.: 88 Cov.: 31 AF XY: 0.00172 AC XY: 1249 AN XY: 726608

African (AFR) AF: 0.0687 AC: 2297 AN: 33440

American (AMR) AF: 0.00312 AC: 139 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5764

European-Non Finnish (NFE) AF: 0.0000774 AC: 86 AN: 1111494

Other (OTH) AF: 0.00394 AC: 238 AN: 60366

GnomAD4 genome AF: 0.0179 AC: 2725 AN: 152306 Hom.: 97 Cov.: 32 AF XY: 0.0168 AC XY: 1250 AN XY: 74464

African (AFR) AF: 0.0622 AC: 2586 AN: 41562

American (AMR) AF: 0.00640 AC: 98 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0103 Hom.: 19

Bravo AF: 0.0206

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Maple syrup urine disease (2)
-	-	2	Maple syrup urine disease type 1A (2)
-	-	2	not specified (2)
-	-	1	BCKDHA-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	10
DANN	Benign	0.84
PhyloP100		2.0
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: rs10404506; hg19: chr19-41925194;