19-41414045-C-T

Variant names:

• chr19-41414045-C-T
• rs199725420
• NM_000709.4:c.376-4C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000709.4(BCKDHA):​c.376-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,302 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (38 hom.)
• Consequence: BCKDHA NM_000709.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001741
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.57
• Publications: 0 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 19-41414045-C-T is Benign according to our data. Variant chr19-41414045-C-T is described in ClinVar as Benign. ClinVar VariationId is 93359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00155 (236/152310) while in subpopulation SAS AF = 0.0222 (107/4826). AF 95% confidence interval is 0.0188. There are 6 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.376-4C>T		splice_region intron	N/A	NP_000700.1
	BCKDHA	NM_001164783.2		c.376-4C>T		splice_region intron	N/A	NP_001158255.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.376-4C>T		splice_region intron	N/A	ENSP00000269980.2
	ENSG00000255730	ENST00000540732.3	TSL:2	c.478-4C>T		splice_region intron	N/A	ENSP00000443246.1
	BCKDHA	ENST00000457836.6	TSL:2	c.310-4C>T		splice_region intron	N/A	ENSP00000416000.2

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00359 AC: 899 AN: 250502 AF XY: 0.00467

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00736

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000850

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00214 AC: 3122 AN: 1460992 Hom.: 38 Cov.: 34 AF XY: 0.00275 AC XY: 1998 AN XY: 726808

African (AFR) AF: 0.000120 AC: 4 AN: 33470

American (AMR) AF: 0.00159 AC: 71 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 173 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0217 AC: 1872 AN: 86250

European-Finnish (FIN) AF: 0.000208 AC: 11 AN: 52888

Middle Eastern (MID) AF: 0.00694 AC: 40 AN: 5760

European-Non Finnish (NFE) AF: 0.000722 AC: 803 AN: 1111706

Other (OTH) AF: 0.00245 AC: 148 AN: 60364

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74468

African (AFR) AF: 0.000241 AC: 10 AN: 41566

American (AMR) AF: 0.00150 AC: 23 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.000990

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.9
DANN	Benign	0.87
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.010		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: rs199725420; hg19: chr19-41919950;