rs11549936

Variant names:

• chr19-41410644-C-A
• rs11549936
• NM_000709.4:c.116C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-41410644-C-A
• chr19-41410644-C-G
• chr19-41410644-C-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.116C>A​(p.Pro39His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,614,072 control chromosomes in the GnomAD database, including 13,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.089 (764 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12540 hom.)
• Consequence: BCKDHA NM_000709.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.80
• 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 (MetaRNN=0.0015936196).
• BP6: Variant 19-41410644-C-A is Benign according to our data. Variant chr19-41410644-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 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.116C>A	p.Pro39His	missense	Exon 2 of 9	NP_000700.1
	BCKDHA	NM_001164783.2		c.116C>A	p.Pro39His	missense	Exon 2 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.116C>A	p.Pro39His	missense	Exon 2 of 9	ENSP00000269980.2
	ENSG00000255730	ENST00000540732.3	TSL:2	c.218C>A	p.Pro73His	missense	Exon 3 of 10	ENSP00000443246.1
	BCKDHA	ENST00000542943.5	TSL:5	c.116C>A	p.Pro39His	missense	Exon 2 of 7	ENSP00000440345.1

Frequencies

GnomAD3 genomes AF: 0.0890 AC: 13543 AN: 152128 Hom.: 765 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.0927

GnomAD2 exomes AF: 0.0988 AC: 24826 AN: 251376 AF XY: 0.104

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.0629

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0741

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.125 AC: 183247 AN: 1461826 Hom.: 12540 Cov.: 34 AF XY: 0.126 AC XY: 91343 AN XY: 727218

African (AFR) AF: 0.0200 AC: 669 AN: 33480

American (AMR) AF: 0.0664 AC: 2969 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3357 AN: 26134

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39700

South Asian (SAS) AF: 0.116 AC: 9997 AN: 86256

European-Finnish (FIN) AF: 0.0739 AC: 3949 AN: 53408

Middle Eastern (MID) AF: 0.128 AC: 740 AN: 5764

European-Non Finnish (NFE) AF: 0.139 AC: 154498 AN: 1111982

Other (OTH) AF: 0.117 AC: 7048 AN: 60386

GnomAD4 genome AF: 0.0889 AC: 13541 AN: 152246 Hom.: 764 Cov.: 32 AF XY: 0.0861 AC XY: 6409 AN XY: 74434

African (AFR) AF: 0.0228 AC: 946 AN: 41550

American (AMR) AF: 0.100 AC: 1529 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.104 AC: 502 AN: 4828

European-Finnish (FIN) AF: 0.0715 AC: 759 AN: 10616

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8964 AN: 67996

Other (OTH) AF: 0.0913 AC: 193 AN: 2114

Alfa AF: 0.115 Hom.: 2612

Bravo AF: 0.0874

TwinsUK AF: 0.142 AC: 528

ALSPAC AF: 0.148 AC: 571

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.136 AC: 1170

ExAC AF: 0.0983 AC: 11938

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.146

EpiControl AF: 0.140

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	0.047
DANN	Benign	0.17
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-1.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.16	N
REVEL	Uncertain	0.35
Sift	Benign	0.70	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.047
MPC		0.20
ClinPred		0.0013	T
GERP RS		-4.9
PromoterAI		0.0078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.034
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11549936; hg19: chr19-41916549; COSMIC: COSV54198869; COSMIC: COSV54198869;