19-41410642-C-T

Variant names:

• chr19-41410642-C-T
• rs11549935
• NM_000709.4:c.114C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000709.4(BCKDHA):​c.114C>T​(p.Pro38Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,614,130 control chromosomes in the GnomAD database, including 559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (282 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (277 hom.)
• Consequence: BCKDHA NM_000709.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.667

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-41410642-C-T is Benign according to our data. Variant chr19-41410642-C-T is described in ClinVar as [Benign]. Clinvar id is 93338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.667 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4	c.114C>T	p.Pro38Pro	synonymous_variant	Exon 2 of 9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.114C>T	p.Pro38Pro	synonymous_variant	Exon 2 of 9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.114C>T	p.Pro38Pro	synonymous_variant	Exon 2 of 9	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.216C>T	p.Pro72Pro	synonymous_variant	Exon 3 of 10	2		ENSP00000443246.1

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5115 AN: 152138 Hom.: 275 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.00953 AC: 2395 AN: 251384 Hom.: 123 AF XY: 0.00722 AC XY: 981 AN XY: 135882

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00772

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000756

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00381 AC: 5565 AN: 1461874 Hom.: 277 Cov.: 32 AF XY: 0.00331 AC XY: 2404 AN XY: 727236

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.00825

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.00950

GnomAD4 genome AF: 0.0338 AC: 5143 AN: 152256 Hom.: 282 Cov.: 31 AF XY: 0.0334 AC XY: 2483 AN XY: 74438

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.00182 Hom.: 1

Bravo AF: 0.0394

EpiCase AF: 0.00120

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 23, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maple syrup urine disease Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Maple syrup urine disease type 1A Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.6
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs11549935; hg19: chr19-41916547;