chr19-41422796-C-T

Variant names:

• chr19-41422796-C-T
• rs284653
• NM_000709.4:c.995+26C>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.995+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,611,234 control chromosomes in the GnomAD database, including 144,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11350 hom., cov: 33)
  • Exomes 𝑓: 0.42 (133409 hom.)
• Consequence: BCKDHA NM_000709.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.248
• Publications: 20 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: ClinGen, G2P, Myriad Women’s Health
• 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 (BayesDel_noAF=-0.86).
• BP6: Variant 19-41422796-C-T is Benign according to our data. Variant chr19-41422796-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.44 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	NM_000709.4	MANE Select	c.995+26C>T		intron	N/A	NP_000700.1
	BCKDHA	NM_001164783.2		c.992+26C>T		intron	N/A	NP_001158255.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.995+26C>T		intron	N/A	ENSP00000269980.2
	ENSG00000255730	ENST00000540732.3	TSL:2	c.1097+26C>T		intron	N/A	ENSP00000443246.1
	BCKDHA	ENST00000919033.1		c.1223+26C>T		intron	N/A	ENSP00000589092.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56258 AN: 151864 Hom.: 11354 Cov.: 33

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.376

GnomAD2 exomes AF: 0.374 AC: 92865 AN: 248348 AF XY: 0.375

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.0804

Gnomad FIN exome AF: 0.519

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.419 AC: 611443 AN: 1459252 Hom.: 133409 Cov.: 67 AF XY: 0.416 AC XY: 301827 AN XY: 725952

African (AFR) AF: 0.248 AC: 8293 AN: 33474

American (AMR) AF: 0.340 AC: 15201 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 10837 AN: 26132

East Asian (EAS) AF: 0.0706 AC: 2801 AN: 39694

South Asian (SAS) AF: 0.278 AC: 23985 AN: 86244

European-Finnish (FIN) AF: 0.516 AC: 26500 AN: 51404

Middle Eastern (MID) AF: 0.397 AC: 2289 AN: 5768

European-Non Finnish (NFE) AF: 0.448 AC: 497791 AN: 1111512

Other (OTH) AF: 0.394 AC: 23746 AN: 60340

GnomAD4 genome AF: 0.370 AC: 56257 AN: 151982 Hom.: 11350 Cov.: 33 AF XY: 0.369 AC XY: 27416 AN XY: 74278

African (AFR) AF: 0.254 AC: 10547 AN: 41456

American (AMR) AF: 0.359 AC: 5486 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1392 AN: 3464

East Asian (EAS) AF: 0.0836 AC: 432 AN: 5170

South Asian (SAS) AF: 0.256 AC: 1232 AN: 4820

European-Finnish (FIN) AF: 0.527 AC: 5558 AN: 10542

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.445 AC: 30206 AN: 67940

Other (OTH) AF: 0.374 AC: 792 AN: 2116

Alfa AF: 0.411 Hom.: 18275

Bravo AF: 0.357

Asia WGS AF: 0.186 AC: 651 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.74
DANN	Benign	0.80
PhyloP100		-0.25
PromoterAI		-0.043	Neutral
Mutation Taster		=100/0	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: rs284653; hg19: chr19-41928701; COSMIC: COSV54197447; COSMIC: COSV54197447;