rs9448884

Variant names:

• chr6-80106779-C-T
• rs9448884
• NM_183050.4:c.86C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_183050.4(BCKDHB):​c.86C>T​(p.Ala29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,592,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.604

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0085271895).
• BP6: Variant 6-80106779-C-T is Benign according to our data. Variant chr6-80106779-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263077.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHB	NM_183050.4	c.86C>T	p.Ala29Val	missense_variant	Exon 1 of 10	ENST00000320393.9	NP_898871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHB	ENST00000320393.9	c.86C>T	p.Ala29Val	missense_variant	Exon 1 of 10	1	NM_183050.4	ENSP00000318351.5
BCKDHB	ENST00000356489.9	c.86C>T	p.Ala29Val	missense_variant	Exon 1 of 11	1		ENSP00000348880.5
BCKDHB	ENST00000369760.8	c.86C>T	p.Ala29Val	missense_variant	Exon 1 of 6	3		ENSP00000358775.4

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000217 AC: 44 AN: 202922 Hom.: 0 AF XY: 0.000188 AC XY: 21 AN XY: 111712

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.0000967

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.000390

GnomAD4 exome AF: 0.000124 AC: 179 AN: 1440254 Hom.: 0 Cov.: 32 AF XY: 0.000116 AC XY: 83 AN XY: 714798

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.0000955

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000689

Gnomad4 OTH exome AF: 0.000371

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 47 AN XY: 74416

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000676

ESP6500AA AF: 0.000941 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000253 AC: 30

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maple syrup urine disease Benign:1

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.18	.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.62	T;.;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.64	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0020	.;B;B
Vest4		0.19
MVP		0.78
MPC		0.20
ClinPred		0.0056	T
GERP RS		1.4
Varity_R		0.031
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs9448884; hg19: chr6-80816496;