chr19-41422819-G-A

Variant names:

• chr19-41422819-G-A
• rs284654
• NM_000709.4:c.995+49G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000709.4(BCKDHA):​c.995+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,609,446 control chromosomes in the GnomAD database, including 296,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30481 hom., cov: 31)
  • Exomes 𝑓: 0.60 (266512 hom.)
• Consequence: BCKDHA NM_000709.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.91
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-41422819-G-A is Benign according to our data. Variant chr19-41422819-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.717 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	NM_000709.4	MANE Select	c.995+49G>A		intron	N/A	NP_000700.1
	BCKDHA	NM_001164783.2		c.992+49G>A		intron	N/A	NP_001158255.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.995+49G>A		intron	N/A	ENSP00000269980.2
	ENSG00000255730	ENST00000540732.3	TSL:2	c.1097+49G>A		intron	N/A	ENSP00000443246.1
	BCKDHA	ENST00000457836.6	TSL:2	c.929+49G>A		intron	N/A	ENSP00000416000.2

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95303 AN: 151664 Hom.: 30457 Cov.: 31

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.623

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.617

GnomAD2 exomes AF: 0.583 AC: 144063 AN: 247068 AF XY: 0.584

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.603

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.603 AC: 878385 AN: 1457664 Hom.: 266512 Cov.: 53 AF XY: 0.602 AC XY: 436531 AN XY: 725144

African (AFR) AF: 0.731 AC: 24475 AN: 33462

American (AMR) AF: 0.478 AC: 21351 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 16237 AN: 26104

East Asian (EAS) AF: 0.459 AC: 18207 AN: 39660

South Asian (SAS) AF: 0.582 AC: 50173 AN: 86214

European-Finnish (FIN) AF: 0.656 AC: 33188 AN: 50628

Middle Eastern (MID) AF: 0.630 AC: 3635 AN: 5766

European-Non Finnish (NFE) AF: 0.607 AC: 674569 AN: 1110886

Other (OTH) AF: 0.606 AC: 36550 AN: 60314

GnomAD4 genome AF: 0.628 AC: 95373 AN: 151782 Hom.: 30481 Cov.: 31 AF XY: 0.627 AC XY: 46467 AN XY: 74118

African (AFR) AF: 0.724 AC: 29985 AN: 41408

American (AMR) AF: 0.549 AC: 8369 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 2161 AN: 3468

East Asian (EAS) AF: 0.433 AC: 2217 AN: 5126

South Asian (SAS) AF: 0.585 AC: 2812 AN: 4808

European-Finnish (FIN) AF: 0.659 AC: 6930 AN: 10512

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.600 AC: 40719 AN: 67902

Other (OTH) AF: 0.616 AC: 1297 AN: 2104

Alfa AF: 0.594 Hom.: 14150

Bravo AF: 0.624

Asia WGS AF: 0.531 AC: 1845 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.073
DANN	Benign	0.53
PhyloP100		-1.9
PromoterAI		0.033	Neutral
Mutation Taster		=100/0	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: rs284654; hg19: chr19-41928724;