6-80203260-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_183050.4(BCKDHB):c.951+48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0633 in 1,287,204 control chromosomes in the GnomAD database, including 4,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (584 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3975 hom.)
• Consequence: BCKDHB NM_183050.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.162

Genes affected

BCKDHB (HGNC:987): (branched chain keto acid dehydrogenase E1 subunit beta) This gene encodes the E1 beta subunit of branched-chain keto acid dehydrogenase, which is a multienzyme complex associated with the inner membrane of mitochondria. This enzyme complex functions in the catabolism of branched-chain amino acids. Mutations in this gene have been associated with maple syrup urine disease (MSUD), type 1B, a disease characterized by a maple syrup odor to the urine in addition to mental and physical retardation and feeding problems. Alternative splicing at this locus results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-80203260-C-T is Benign according to our data. Variant chr6-80203260-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHB	NM_183050.4	c.951+48C>T		intron_variant		ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.951+48C>T		intron_variant		1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.951+48C>T		intron_variant		1		P1
BCKDHB	ENST00000468520.1	n.111+48C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10916 AN: 151874 Hom.: 585 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0756

GnomAD3 exomes AF: 0.0781 AC: 19391 AN: 248228 Hom.: 1373 AF XY: 0.0854 AC XY: 11457 AN XY: 134210

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0289

Gnomad ASJ exome AF: 0.0598

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.236

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0453

Gnomad OTH exome AF: 0.0666

GnomAD4 exome AF: 0.0622 AC: 70557 AN: 1135214 Hom.: 3975 Cov.: 16 AF XY: 0.0682 AC XY: 39558 AN XY: 580082

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0302

Gnomad4 ASJ exome AF: 0.0638

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.0383

Gnomad4 NFE exome AF: 0.0426

Gnomad4 OTH exome AF: 0.0691

GnomAD4 genome AF: 0.0719 AC: 10926 AN: 151990 Hom.: 584 Cov.: 32 AF XY: 0.0743 AC XY: 5517 AN XY: 74282

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0387

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.0384

Gnomad4 NFE AF: 0.0467

Gnomad4 OTH AF: 0.0795

Alfa AF: 0.0409 Hom.: 45

Bravo AF: 0.0689

Asia WGS AF: 0.191 AC: 667 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2013	- -

Maple syrup urine disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	5.9
Dann	Benign	0.45

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: rs3749896; hg19: chr6-80912977; COSMIC: COSV57510907;