6-80127536-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_183050.4(BCKDHB):​c.197-11G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,555,556 control chromosomes in the GnomAD database, including 143,841 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16096 hom., cov: 32)
  • Exomes 𝑓: 0.46 (127745 hom.)
• Consequence: BCKDHB NM_183050.4 intron
• Scores: Splicing: ADA: 0.00001270
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-80127536-G-T is Benign according to our data. Variant chr6-80127536-G-T is described in ClinVar as Benign. ClinVar VariationId is 96572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.676 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.197-11G>T		intron	N/A	NP_898871.1
	BCKDHB	NM_001424035.1		c.197-11G>T		intron	N/A	NP_001410964.1
	BCKDHB	NM_000056.5		c.197-11G>T		intron	N/A	NP_000047.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.197-11G>T		intron	N/A	ENSP00000318351.5
	BCKDHB	ENST00000356489.9	TSL:1	c.197-11G>T		intron	N/A	ENSP00000348880.5
	BCKDHB	ENST00000929318.1		c.197-11G>T		intron	N/A	ENSP00000599377.1

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66288 AN: 150356 Hom.: 16077 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.696

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.571

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.491

GnomAD2 exomes AF: 0.460 AC: 107851 AN: 234524 AF XY: 0.461

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.562

Gnomad ASJ exome AF: 0.473

Gnomad EAS exome AF: 0.572

Gnomad FIN exome AF: 0.445

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.476

GnomAD4 exome AF: 0.461 AC: 648014 AN: 1405096 Hom.: 127745 Cov.: 31 AF XY: 0.464 AC XY: 324403 AN XY: 699316

African (AFR) AF: 0.213 AC: 6817 AN: 31994

American (AMR) AF: 0.595 AC: 25322 AN: 42544

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 12521 AN: 25170

East Asian (EAS) AF: 0.600 AC: 22419 AN: 37382

South Asian (SAS) AF: 0.559 AC: 45846 AN: 82068

European-Finnish (FIN) AF: 0.457 AC: 23692 AN: 51812

Middle Eastern (MID) AF: 0.543 AC: 3026 AN: 5572

European-Non Finnish (NFE) AF: 0.449 AC: 481186 AN: 1070642

Other (OTH) AF: 0.469 AC: 27185 AN: 57912

GnomAD4 genome AF: 0.441 AC: 66329 AN: 150460 Hom.: 16096 Cov.: 32 AF XY: 0.449 AC XY: 32985 AN XY: 73460

African (AFR) AF: 0.226 AC: 9253 AN: 40902

American (AMR) AF: 0.598 AC: 9044 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1887 AN: 3454

East Asian (EAS) AF: 0.695 AC: 3578 AN: 5146

South Asian (SAS) AF: 0.663 AC: 3178 AN: 4790

European-Finnish (FIN) AF: 0.491 AC: 5001 AN: 10188

Middle Eastern (MID) AF: 0.580 AC: 166 AN: 286

European-Non Finnish (NFE) AF: 0.484 AC: 32695 AN: 67570

Other (OTH) AF: 0.495 AC: 1034 AN: 2088

Alfa AF: 0.176 Hom.: 1176

Bravo AF: 0.435

Asia WGS AF: 0.653 AC: 2269 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Maple syrup urine disease (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.28
DANN	Benign	0.56
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
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; COSMIC: COSV57509708;