19-41423083-A-G

Variant names:

• chr19-41423083-A-G
• rs61736656
• NM_000709.4:c.1081A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000269980.7(BCKDHA):​c.1081A>G​(p.Ile361Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000679 in 1,582,178 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (3 hom.)
• Consequence: BCKDHA ENST00000269980.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 8.53
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012824625).
• BP6: Variant 19-41423083-A-G is Benign according to our data. Variant chr19-41423083-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 457140.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000269980.7. 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.1081A>G	p.Ile361Val	missense	Exon 8 of 9	NP_000700.1
	BCKDHA	NM_001164783.2		c.1078A>G	p.Ile360Val	missense	Exon 8 of 9	NP_001158255.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.1081A>G	p.Ile361Val	missense	Exon 8 of 9	ENSP00000269980.2
	ENSG00000255730	ENST00000540732.3	TSL:2	c.1183A>G	p.Ile395Val	missense	Exon 9 of 10	ENSP00000443246.1
	BCKDHA	ENST00000457836.6	TSL:2	c.1090A>G	p.Ile364Val	missense	Exon 8 of 9	ENSP00000416000.2

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 151956 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000948 AC: 186 AN: 196186 AF XY: 0.00104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000355

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.0000683

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000461

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000696 AC: 995 AN: 1430104 Hom.: 3 Cov.: 35 AF XY: 0.000698 AC XY: 495 AN XY: 708734

African (AFR) AF: 0.0000304 AC: 1 AN: 32900

American (AMR) AF: 0.000153 AC: 6 AN: 39314

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 372 AN: 25486

East Asian (EAS) AF: 0.00 AC: 0 AN: 38152

South Asian (SAS) AF: 0.0000366 AC: 3 AN: 81968

European-Finnish (FIN) AF: 0.0000390 AC: 2 AN: 51330

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5652

European-Non Finnish (NFE) AF: 0.000481 AC: 527 AN: 1096058

Other (OTH) AF: 0.00138 AC: 82 AN: 59244

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152074 Hom.: 0 Cov.: 33 AF XY: 0.000471 AC XY: 35 AN XY: 74358

African (AFR) AF: 0.0000723 AC: 3 AN: 41480

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67988

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000958 Hom.: 1

Bravo AF: 0.000570

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000655 AC: 79

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Maple syrup urine disease (3)
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.013	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.5	L
PhyloP100		8.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.72	N
REVEL	Pathogenic	0.65
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Polyphen		0.39	B
Vest4		0.55
MVP		0.88
MPC		1.1
ClinPred		0.057	T
GERP RS		5.8
PromoterAI		-0.0086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.35
gMVP		0.56
Mutation Taster		=79/21	polymorphism

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: rs61736656; hg19: chr19-41928988;