rs284654

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-41422819-G-A
• chr19-41422819-G-T

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

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]

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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4	c.995+49G>A		intron_variant	Intron 7 of 8	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.992+49G>A		intron_variant	Intron 7 of 8		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.995+49G>A		intron_variant	Intron 7 of 8	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.1097+49G>A		intron_variant	Intron 8 of 9	2		ENSP00000443246.1

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

Gnomad4 AFR exome AF: 0.731 AC: 24475 AN: 33462

Gnomad4 AMR exome AF: 0.478 AC: 21351 AN: 44630

Gnomad4 ASJ exome AF: 0.622 AC: 16237 AN: 26104

Gnomad4 EAS exome AF: 0.459 AC: 18207 AN: 39660

Gnomad4 SAS exome AF: 0.582 AC: 50173 AN: 86214

Gnomad4 FIN exome AF: 0.656 AC: 33188 AN: 50628

Gnomad4 NFE exome AF: 0.607 AC: 674569 AN: 1110886

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.724 AC: 0.724135 AN: 0.724135

Gnomad4 AMR AF: 0.549 AC: 0.548571 AN: 0.548571

Gnomad4 ASJ AF: 0.623 AC: 0.623126 AN: 0.623126

Gnomad4 EAS AF: 0.433 AC: 0.432501 AN: 0.432501

Gnomad4 SAS AF: 0.585 AC: 0.584859 AN: 0.584859

Gnomad4 FIN AF: 0.659 AC: 0.659247 AN: 0.659247

Gnomad4 NFE AF: 0.600 AC: 0.599673 AN: 0.599673

Gnomad4 OTH AF: 0.616 AC: 0.616445 AN: 0.616445

Alfa AF: 0.594 Hom.: 14150

Bravo AF: 0.624

Asia WGS AF: 0.531 AC: 1845 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maple syrup urine disease Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.073
DANN	Benign	0.53
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

Publications

LitVar

Other links and lift over

dbSNP: rs284654; hg19: chr19-41928724;