chr6-80106695-T-TGGCGGTTGTAGC

Variant names:

• chr6-80106695-T-TGGCGGTTGTAGC
• rs1554180793
• NM_183050.4:c.8_19dupTTGTAGCGGCGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_183050.4(BCKDHB):​c.8_19dupTTGTAGCGGCGG​(p.Val3_Ala6dup) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A7A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB NM_183050.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.46
• Publications: 0 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: G2P, Myriad Women’s Health, ClinGen
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_183050.4.

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.8_19dupTTGTAGCGGCGG	p.Val3_Ala6dup	disruptive_inframe_insertion	Exon 1 of 10	NP_898871.1	P21953-1
	BCKDHB	NM_001424035.1		c.8_19dupTTGTAGCGGCGG	p.Val3_Ala6dup	disruptive_inframe_insertion	Exon 1 of 10	NP_001410964.1
	BCKDHB	NM_000056.5		c.8_19dupTTGTAGCGGCGG	p.Val3_Ala6dup	disruptive_inframe_insertion	Exon 1 of 11	NP_000047.1	A0A140VKB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.8_19dupTTGTAGCGGCGG	p.Val3_Ala6dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000318351.5	P21953-1
	BCKDHB	ENST00000356489.9	TSL:1	c.8_19dupTTGTAGCGGCGG	p.Val3_Ala6dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000348880.5	P21953-1
	BCKDHB	ENST00000929318.1		c.8_19dupTTGTAGCGGCGG	p.Val3_Ala6dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000599377.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554180793; hg19: chr6-80816412;