rs4502885

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-80344798-G-A
• chr6-80344798-G-C
• chr6-80344798-G-T

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHB	NM_183050.4	c.*994G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9	c.*994G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_183050.4	ENSP00000318351.5
BCKDHB	ENST00000356489.9	c.*8+986G>A		intron_variant	Intron 10 of 10	1		ENSP00000348880.5
BCKDHB	ENST00000491328.1	n.242+986G>A		intron_variant	Intron 1 of 1	2

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maple syrup urine disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;