NM_183050.4:c.197-11G>A

Variant names:

• chr6-80127536-G-A
• rs9448894
• NM_183050.4:c.197-11G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_183050.4(BCKDHB):​c.197-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,413,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BCKDHB NM_183050.4 intron
• Scores: Splicing: ADA: 0.00006989
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.218
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-80127536-G-A is Benign according to our data. Variant chr6-80127536-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2889200.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHB	NM_183050.4	c.197-11G>A		intron_variant	Intron 1 of 9	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9	c.197-11G>A		intron_variant	Intron 1 of 9	1	NM_183050.4	ENSP00000318351.5
BCKDHB	ENST00000356489.9	c.197-11G>A		intron_variant	Intron 1 of 10	1		ENSP00000348880.5
BCKDHB	ENST00000369760.8	c.197-11G>A		intron_variant	Intron 1 of 5	3		ENSP00000358775.4
BCKDHB	ENST00000486968.1	n.111-11G>A		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000426 AC: 1 AN: 234524 AF XY: 0.00000789

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000929

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1413562 Hom.: 0 Cov.: 31 AF XY: 0.00000284 AC XY: 2 AN XY: 703310

African (AFR) AF: 0.00 AC: 0 AN: 32226

American (AMR) AF: 0.00 AC: 0 AN: 42640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25266

East Asian (EAS) AF: 0.00 AC: 0 AN: 37468

South Asian (SAS) AF: 0.00 AC: 0 AN: 82300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1077938

Other (OTH) AF: 0.00 AC: 0 AN: 58210

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1176

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maple syrup urine disease Benign:1

Feb 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.30
DANN	Benign	0.49
PhyloP100		-0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.0
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: rs9448894; hg19: chr6-80837253;