rs587783003

Variant names:

• chr3-15642053-C-G
• rs587783003
• NM_001370658.1:c.395C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-15642053-C-G
• chr3-15642053-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001370658.1(BTD):​c.395C>G​(p.Thr132Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

BTD (HGNC:1122): (biotinidase) The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]

BTD Gene-Disease associations (from GenCC):

• biotinidase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 88 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -0.52516 (below the threshold of 3.09). Trascript score misZ: 0.15371 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, biotinidase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 3-15642053-C-G is Pathogenic according to our data. Variant chr3-15642053-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 156001.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.395C>G	p.Thr132Arg	missense_variant	Exon 3 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.395C>G	p.Thr132Arg	missense_variant	Exon 3 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Apr 30, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data are high quality. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BTD: PM2, PM5, PM3:Supporting -

Biotinidase deficiency Pathogenic:1

-

Molecular Genetics Diagnostic Laboratory, Detroit Medical Center University Laboratories

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	.;.;D;.;.;.;.;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.1	.;D;.;.;.;.;D;D;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;D;.;.;.;.;D;T;D;.
Sift4G	Uncertain	0.0090	.;D;.;.;.;.;T;T;D;.
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.
Vest4		0.97, 0.98, 0.98
MutPred		0.73		.;.;Gain of MoRF binding (P = 0.1705);.;Gain of MoRF binding (P = 0.1705);.;.;.;.;.;
MVP		0.97
MPC		0.44
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs587783003; hg19: chr3-15683560;