6-80203260-C-T

Variant names:

• chr6-80203260-C-T
• rs3749896
• NM_183050.4:c.951+48C>T

Variant summary

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

The NM_001424044.1(BCKDHB):​c.*42C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0633 in 1,287,204 control chromosomes in the GnomAD database, including 4,559 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 (584 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3975 hom.)
• Consequence: BCKDHB NM_001424044.1 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.162
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-80203260-C-T is Benign according to our data. Variant chr6-80203260-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424044.1. 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.951+48C>T		intron	N/A	NP_898871.1	P21953-1
	BCKDHB	NM_001424044.1		c.*42C>T		3_prime_UTR	Exon 8 of 8	NP_001410973.1
	BCKDHB	NM_001424035.1		c.951+48C>T		intron	N/A	NP_001410964.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.951+48C>T		intron	N/A	ENSP00000318351.5	P21953-1
	BCKDHB	ENST00000356489.9	TSL:1	c.951+48C>T		intron	N/A	ENSP00000348880.5	P21953-1
	BCKDHB	ENST00000929318.1		c.951+48C>T		intron	N/A	ENSP00000599377.1

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10916 AN: 151874 Hom.: 585 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0756

GnomAD2 exomes AF: 0.0781 AC: 19391 AN: 248228 AF XY: 0.0854

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0289

Gnomad ASJ exome AF: 0.0598

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0453

Gnomad OTH exome AF: 0.0666

GnomAD4 exome AF: 0.0622 AC: 70557 AN: 1135214 Hom.: 3975 Cov.: 16 AF XY: 0.0682 AC XY: 39558 AN XY: 580082

African (AFR) AF: 0.110 AC: 2967 AN: 26982

American (AMR) AF: 0.0302 AC: 1334 AN: 44134

Ashkenazi Jewish (ASJ) AF: 0.0638 AC: 1534 AN: 24052

East Asian (EAS) AF: 0.155 AC: 5887 AN: 38098

South Asian (SAS) AF: 0.229 AC: 18219 AN: 79434

European-Finnish (FIN) AF: 0.0383 AC: 2031 AN: 53040

Middle Eastern (MID) AF: 0.0860 AC: 443 AN: 5154

European-Non Finnish (NFE) AF: 0.0426 AC: 34706 AN: 814602

Other (OTH) AF: 0.0691 AC: 3436 AN: 49718

GnomAD4 genome AF: 0.0719 AC: 10926 AN: 151990 Hom.: 584 Cov.: 32 AF XY: 0.0743 AC XY: 5517 AN XY: 74282

African (AFR) AF: 0.106 AC: 4389 AN: 41456

American (AMR) AF: 0.0387 AC: 591 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3470

East Asian (EAS) AF: 0.137 AC: 710 AN: 5170

South Asian (SAS) AF: 0.237 AC: 1140 AN: 4820

European-Finnish (FIN) AF: 0.0384 AC: 406 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0467 AC: 3171 AN: 67916

Other (OTH) AF: 0.0795 AC: 168 AN: 2112

Alfa AF: 0.0457 Hom.: 77

Bravo AF: 0.0689

Asia WGS AF: 0.191 AC: 667 AN: 3478

ClinVar

ClinVar submissions

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	-0.86
CADD	Benign	5.9
DANN	Benign	0.45
PhyloP100		-0.16
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: rs3749896; hg19: chr6-80912977; COSMIC: COSV57510907;