19-41398260-C-T

Variant names:

• chr19-41398260-C-T
• rs3810174
• NM_000709.4:c.108+325C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000709.4(BCKDHA):​c.108+325C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 151,874 control chromosomes in the GnomAD database, including 29,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.62 (29646 hom., cov: 30)
• Consequence: BCKDHA NM_000709.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.482
• Publications: 13 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, ClinGen, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-41398260-C-T is Benign according to our data. Variant chr19-41398260-C-T is described in ClinVar as Benign. ClinVar VariationId is 680490.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 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.108+325C>T		intron	N/A	NP_000700.1	P12694-1
	BCKDHA	NM_001164783.2		c.108+325C>T		intron	N/A	NP_001158255.1	Q59EI3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.108+325C>T		intron	N/A	ENSP00000269980.2	P12694-1
	ENSG00000255730	ENST00000540732.3	TSL:2	c.211-12377C>T		intron	N/A	ENSP00000443246.1	F5H5P2
	BCKDHA	ENST00000919033.1		c.108+325C>T		intron	N/A	ENSP00000589092.1

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94078 AN: 151758 Hom.: 29625 Cov.: 30

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.607

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.620 AC: 94144 AN: 151874 Hom.: 29646 Cov.: 30 AF XY: 0.618 AC XY: 45870 AN XY: 74204

African (AFR) AF: 0.703 AC: 29097 AN: 41410

American (AMR) AF: 0.543 AC: 8292 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2155 AN: 3468

East Asian (EAS) AF: 0.429 AC: 2207 AN: 5146

South Asian (SAS) AF: 0.589 AC: 2833 AN: 4810

European-Finnish (FIN) AF: 0.660 AC: 6949 AN: 10532

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.595 AC: 40448 AN: 67928

Other (OTH) AF: 0.608 AC: 1282 AN: 2110

Alfa AF: 0.598 Hom.: 21820

Bravo AF: 0.615

Asia WGS AF: 0.525 AC: 1826 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.61
PhyloP100		-0.48
PromoterAI		0.065	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: rs3810174; hg19: chr19-41904165;