6-80331150-C-T

Variant names:

• chr6-80331150-C-T
• rs10455370
• NM_183050.4:c.1039-12514C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_183050.4(BCKDHB):​c.1039-12514C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 151,998 control chromosomes in the GnomAD database, including 15,404 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (15404 hom., cov: 32)
• Consequence: BCKDHB NM_183050.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• maple syrup urine disease type 1B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women's Health, ClinGen
• maple syrup urine disease

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183050.4. 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
	BCKDHB	NM_183050.4	MANE Select	c.1039-12514C>T		intron	N/A	NP_898871.1	P21953-1
	BCKDHB	NM_001424035.1		c.1039-23103C>T		intron	N/A	NP_001410964.1
	BCKDHB	NM_000056.5		c.1039-12514C>T		intron	N/A	NP_000047.1	A0A140VKB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.1039-12514C>T		intron	N/A	ENSP00000318351.5	P21953-1
	BCKDHB	ENST00000356489.9	TSL:1	c.1039-12514C>T		intron	N/A	ENSP00000348880.5	P21953-1
	BCKDHB	ENST00000929318.1		c.1158+4494C>T		intron	N/A	ENSP00000599377.1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62448 AN: 151880 Hom.: 15390 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.411 AC: 62476 AN: 151998 Hom.: 15404 Cov.: 32 AF XY: 0.414 AC XY: 30788 AN XY: 74294

African (AFR) AF: 0.120 AC: 4988 AN: 41478

American (AMR) AF: 0.585 AC: 8927 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 2053 AN: 3466

East Asian (EAS) AF: 0.533 AC: 2750 AN: 5160

South Asian (SAS) AF: 0.452 AC: 2173 AN: 4808

European-Finnish (FIN) AF: 0.508 AC: 5367 AN: 10566

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34638 AN: 67956

Other (OTH) AF: 0.456 AC: 962 AN: 2110

Alfa AF: 0.486 Hom.: 16689

Bravo AF: 0.405

Asia WGS AF: 0.486 AC: 1690 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Benign	0.72
PhyloP100		1.1
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10455370;

hg19: chr6-81040867;