rs73479953

Variant names:

• chr6-80167654-C-T
• rs73479953
• NM_183050.4:c.344-24C>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.344-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,583,272 control chromosomes in the GnomAD database, including 5,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (580 hom., cov: 32)
  • Exomes 𝑓: 0.059 (4475 hom.)
• Consequence: BCKDHB NM_183050.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.74
• Publications: 3 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=-0.91).
• BP6: Variant 6-80167654-C-T is Benign according to our data. Variant chr6-80167654-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.226 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	NM_183050.4	MANE Select	c.344-24C>T		intron	N/A	NP_898871.1
	BCKDHB	NM_001424035.1		c.344-24C>T		intron	N/A	NP_001410964.1
	BCKDHB	NM_000056.5		c.344-24C>T		intron	N/A	NP_000047.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.344-24C>T		intron	N/A	ENSP00000318351.5
	BCKDHB	ENST00000356489.9	TSL:1	c.344-24C>T		intron	N/A	ENSP00000348880.5
	BCKDHB	ENST00000369760.8	TSL:3	c.344-24C>T		intron	N/A	ENSP00000358775.4

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10905 AN: 152046 Hom.: 581 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0384

Gnomad ASJ AF: 0.0678

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0756

GnomAD2 exomes AF: 0.0777 AC: 19425 AN: 250108 AF XY: 0.0850

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0284

Gnomad ASJ exome AF: 0.0600

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.0450

Gnomad OTH exome AF: 0.0658

GnomAD4 exome AF: 0.0594 AC: 84971 AN: 1431106 Hom.: 4475 Cov.: 31 AF XY: 0.0647 AC XY: 46151 AN XY: 713680

African (AFR) AF: 0.111 AC: 3617 AN: 32654

American (AMR) AF: 0.0300 AC: 1341 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 1669 AN: 25956

East Asian (EAS) AF: 0.154 AC: 6080 AN: 39454

South Asian (SAS) AF: 0.229 AC: 19600 AN: 85424

European-Finnish (FIN) AF: 0.0379 AC: 2015 AN: 53222

Middle Eastern (MID) AF: 0.0858 AC: 489 AN: 5702

European-Non Finnish (NFE) AF: 0.0424 AC: 46032 AN: 1084646

Other (OTH) AF: 0.0695 AC: 4128 AN: 59400

GnomAD4 genome AF: 0.0717 AC: 10915 AN: 152166 Hom.: 580 Cov.: 32 AF XY: 0.0741 AC XY: 5514 AN XY: 74372

African (AFR) AF: 0.105 AC: 4377 AN: 41518

American (AMR) AF: 0.0384 AC: 586 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0678 AC: 235 AN: 3466

East Asian (EAS) AF: 0.137 AC: 709 AN: 5168

South Asian (SAS) AF: 0.237 AC: 1143 AN: 4814

European-Finnish (FIN) AF: 0.0384 AC: 407 AN: 10594

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0467 AC: 3175 AN: 68006

Other (OTH) AF: 0.0795 AC: 168 AN: 2114

Alfa AF: 0.0596 Hom.: 78

Bravo AF: 0.0689

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Maple syrup urine disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.30
DANN	Benign	0.26
PhyloP100		-1.7
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: rs73479953; hg19: chr6-80877371; COSMIC: COSV57510898;