6-80106711-G-T

Variant names:

• chr6-80106711-G-T
• rs2127698696
• NM_183050.4:c.18G>T

Variant summary

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

The NM_001424043.1(BCKDHB):​c.-147G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000786 in 1,399,752 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: 0.0000079 (0 hom.)
• Consequence: BCKDHB NM_001424043.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.550
• 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: 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=-0.72).
• BP6: Variant 6-80106711-G-T is Benign according to our data. Variant chr6-80106711-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1555745.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424043.1. 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.18G>T	p.Ala6Ala	synonymous	Exon 1 of 10	NP_898871.1	P21953-1
	BCKDHB	NM_001424043.1		c.-147G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001410972.1	B7ZB80
	BCKDHB	NM_001424035.1		c.18G>T	p.Ala6Ala	synonymous	Exon 1 of 10	NP_001410964.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.18G>T	p.Ala6Ala	synonymous	Exon 1 of 10	ENSP00000318351.5	P21953-1
	BCKDHB	ENST00000356489.9	TSL:1	c.18G>T	p.Ala6Ala	synonymous	Exon 1 of 11	ENSP00000348880.5	P21953-1
	BCKDHB	ENST00000929318.1		c.18G>T	p.Ala6Ala	synonymous	Exon 1 of 11	ENSP00000599377.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1399752 Hom.: 0 Cov.: 32 AF XY: 0.00000579 AC XY: 4 AN XY: 690850

African (AFR) AF: 0.00 AC: 0 AN: 31618

American (AMR) AF: 0.00 AC: 0 AN: 36096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35972

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4180

European-Non Finnish (NFE) AF: 0.00000925 AC: 10 AN: 1080518

Other (OTH) AF: 0.00 AC: 0 AN: 57916

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.7
DANN	Benign	0.66
PhyloP100		-0.55
PromoterAI		-0.067	Neutral

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: rs2127698696; hg19: chr6-80816428;