NM_183050.4:c.*994G>A

Variant names:

• chr6-80344798-G-A
• rs4502885
• NM_183050.4:c.*994G>A

Variant summary

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

The NM_183050.4(BCKDHB):​c.*994G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 152,096 control chromosomes in the GnomAD database, including 46,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.78 (46288 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: BCKDHB NM_183050.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.217
• Publications: 8 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: ClinGen, G2P, Myriad Women’s Health
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-80344798-G-A is Benign according to our data. Variant chr6-80344798-G-A is described in ClinVar as Benign. ClinVar VariationId is 358196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.823 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.*994G>A		3_prime_UTR	Exon 10 of 10	NP_898871.1
	BCKDHB	NM_001424039.1		c.*1179G>A		3_prime_UTR	Exon 11 of 11	NP_001410968.1
	BCKDHB	NM_001318975.1		c.*994G>A		3_prime_UTR	Exon 10 of 10	NP_001305904.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.*994G>A		3_prime_UTR	Exon 10 of 10	ENSP00000318351.5
	BCKDHB	ENST00000356489.9	TSL:1	c.*8+986G>A		intron	N/A	ENSP00000348880.5
	BCKDHB	ENST00000929318.1		c.*994G>A		3_prime_UTR	Exon 11 of 11	ENSP00000599377.1

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118129 AN: 151978 Hom.: 46262 Cov.: 32

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.835

Gnomad ASJ AF: 0.847

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.798

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.777 AC: 118212 AN: 152096 Hom.: 46288 Cov.: 32 AF XY: 0.775 AC XY: 57615 AN XY: 74340

African (AFR) AF: 0.688 AC: 28517 AN: 41464

American (AMR) AF: 0.835 AC: 12764 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.847 AC: 2941 AN: 3472

East Asian (EAS) AF: 0.751 AC: 3886 AN: 5172

South Asian (SAS) AF: 0.611 AC: 2943 AN: 4818

European-Finnish (FIN) AF: 0.802 AC: 8470 AN: 10566

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.824 AC: 56014 AN: 67998

Other (OTH) AF: 0.798 AC: 1687 AN: 2114

Alfa AF: 0.813 Hom.: 64243

Bravo AF: 0.779

Asia WGS AF: 0.672 AC: 2336 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Maple syrup urine disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.73
PhyloP100		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs4502885; hg19: chr6-81054515;