rs111903796

chr6-80171397-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_183050.4(BCKDHB):c.742+7A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,510,058 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: BCKDHB NM_183050.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004768
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.879

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-80171397-A-T is Benign according to our data. Variant chr6-80171397-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 384206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00174 (264/151902) while in subpopulation AFR AF= 0.00603 (250/41434). AF 95% confidence interval is 0.00542. There are 1 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHB	NM_183050.4	c.742+7A>T		splice_region_variant, intron_variant		ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.742+7A>T		splice_region_variant, intron_variant		1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.742+7A>T		splice_region_variant, intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 256 AN: 151782 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000479 AC: 113 AN: 235840 Hom.: 0 AF XY: 0.000429 AC XY: 55 AN XY: 128204

Gnomad AFR exome AF: 0.00632

Gnomad AMR exome AF: 0.000393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000173

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000377

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000190 AC: 258 AN: 1358156 Hom.: 2 Cov.: 21 AF XY: 0.000181 AC XY: 123 AN XY: 680380

Gnomad4 AFR exome AF: 0.00617

Gnomad4 AMR exome AF: 0.000370

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000683

Gnomad4 OTH exome AF: 0.000673

GnomAD4 genome AF: 0.00174 AC: 264 AN: 151902 Hom.: 1 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74278

Gnomad4 AFR AF: 0.00603

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.000603 Hom.: 0

Bravo AF: 0.00180

Asia WGS AF: 0.00232 AC: 8 AN: 3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Maple syrup urine disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.060
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
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

Publications

LitVar

Other links and lift over

dbSNP: rs111903796; hg19: chr6-80881114;