6-80106772-CCTGGCGCGGGG-C

Position:

chr6-80106772-CCTGGCGCGGGG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_183050.4(BCKDHB):c.93_103del(p.Ala32PhefsTer48) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,589,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BCKDHB
NM_183050.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.48

Variant links:

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]

BCKDHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-80106772-CCTGGCGCGGGG-C is Pathogenic according to our data. Variant chr6-80106772-CCTGGCGCGGGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 96618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCKDHB	NM_183050.4 linkuse as main transcript	c.93_103del	p.Ala32PhefsTer48	frameshift_variant	1/10	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9 linkuse as main transcript	c.93_103del	p.Ala32PhefsTer48	frameshift_variant	1/10	1	NM_183050.4	ENSP00000318351	P1	P21953-1
BCKDHB	ENST00000356489.9 linkuse as main transcript	c.93_103del	p.Ala32PhefsTer48	frameshift_variant	1/11	1		ENSP00000348880	P1	P21953-1
BCKDHB	ENST00000369760.8 linkuse as main transcript	c.93_103del	p.Ala32PhefsTer48	frameshift_variant	1/6	3		ENSP00000358775		P21953-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000101

AC:

AN:

198414

Hom.:

AF XY:

0.0000183

AC XY:

AN XY:

109044

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000240

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1436956

Hom.:

AF XY:

0.0000126

AC XY:

AN XY:

712878

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000483

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000145

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 29, 2024	The p.Ala32PhefsX48 variant in BCKDHB has been reported in the homozygous and compound heterozygous state in at least 4 individuals (2 homozygotes, 2 compound heterozygote with at least one disease causing allele in BCKDHB) with maple syrup urine disease (MSUD) and segregated with disease in 2 affected relatives from 1 family (Nobukuni 1991 PMID: 2022752, Rodriguez-Pombo 2006 PMID: PMID: 16786533, Tabbouche 2014 PMID: 27896100, Yang 2019 PMID: 31112740). It at least 2 individuals, BCKDH enzyme activity was severely reduced (Nobukuni 1991 PMID: 2022752, Rodriguez-Pombo 2006 PMID: 16786533). The variant was also detected in the heterozygous state in 2 families with MSUD where a second variant was not identified (Parella 1994 PMID: 7707687). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 96618) and has also been identified in 0.002% (1/41438) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is a deletion of 11 base pairs and is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at amino acid 32 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the BCKDHB gene is an established disease mechanism in autosomal recessive MSUD. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MSUD. ACMG/AMP Criteria applied: PVS1, PM3_Moderate, PP1, PM2_Supporting, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Ala32Phefs*48) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs751389206, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 2022752, 31112740). It has also been observed to segregate with disease in related individuals. This variant is also known as c.92_102del11. ClinVar contains an entry for this variant (Variation ID: 96618). For these reasons, this variant has been classified as Pathogenic. -

Maple syrup urine disease type 1B

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2018	Variant summary: BCKDHB c.93_103del11 (p.Ala32PhefsX48) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 234612 control chromosomes (gnomAD). c.93_103del11 has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease (Tabbouche_2014, Rodriguez-Pombo_2006, Parrella_1994, Nobukuni_1991). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant caused a severe decrease in BCKDH enzyme activity and also, resulted in absence of E1 beta subunit of BCKDH while the E1 alpha subunit of BCKDH was markedly reduced (Nobukuni_1991). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 16, 2016

- -

Maple syrup urine disease type 1A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over