rs3217385

Variant names:

• chr19-41422962-G-GC
• rs3217385
• NM_000709.4:c.996-33dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000709.4(BCKDHA):​c.996-33dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,596,250 control chromosomes in the GnomAD database, including 301,111 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33815 hom., cov: 0)
  • Exomes 𝑓: 0.61 (267296 hom.)
• Consequence: BCKDHA NM_000709.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.230
• Publications: 8 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 -16 ACMG points.

• BP6: Variant 19-41422962-G-GC is Benign according to our data. Variant chr19-41422962-G-GC is described in ClinVar as Benign. ClinVar VariationId is 93389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4	c.996-33dupC		intron_variant	Intron 7 of 8	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.993-33dupC		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.996-33dupC		intron_variant	Intron 7 of 8	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.1098-33dupC		intron_variant	Intron 8 of 9	2		ENSP00000443246.1

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99667 AN: 151840 Hom.: 33773 Cov.: 0

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.638

GnomAD2 exomes AF: 0.590 AC: 129959 AN: 220434 AF XY: 0.589

Gnomad AFR exome AF: 0.823

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.425

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.604

Gnomad OTH exome AF: 0.607

GnomAD4 exome AF: 0.606 AC: 874637 AN: 1444292 Hom.: 267296 Cov.: 36 AF XY: 0.604 AC XY: 433268 AN XY: 716882

African (AFR) AF: 0.832 AC: 27533 AN: 33112

American (AMR) AF: 0.483 AC: 20350 AN: 42122

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16036 AN: 25730

East Asian (EAS) AF: 0.458 AC: 17787 AN: 38844

South Asian (SAS) AF: 0.581 AC: 48820 AN: 83956

European-Finnish (FIN) AF: 0.654 AC: 34122 AN: 52156

Middle Eastern (MID) AF: 0.635 AC: 3651 AN: 5746

European-Non Finnish (NFE) AF: 0.607 AC: 669742 AN: 1102950

Other (OTH) AF: 0.613 AC: 36596 AN: 59676

GnomAD4 genome AF: 0.657 AC: 99762 AN: 151958 Hom.: 33815 Cov.: 0 AF XY: 0.654 AC XY: 48545 AN XY: 74270

African (AFR) AF: 0.821 AC: 34012 AN: 41450

American (AMR) AF: 0.560 AC: 8543 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2175 AN: 3470

East Asian (EAS) AF: 0.433 AC: 2225 AN: 5142

South Asian (SAS) AF: 0.587 AC: 2826 AN: 4816

European-Finnish (FIN) AF: 0.660 AC: 6962 AN: 10550

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

European-Non Finnish (NFE) AF: 0.600 AC: 40783 AN: 67944

Other (OTH) AF: 0.638 AC: 1349 AN: 2114

Alfa AF: 0.624 Hom.: 5474

Bravo AF: 0.656

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 23, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maple syrup urine disease Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BCKDHA-related disorder Benign:1

May 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=12/188	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: rs3217385; hg19: chr19-41928867; COSMIC: COSV54195561; COSMIC: COSV54195561;