NM_001370658.1:c.132G>C

Variant names:

• chr3-15635571-G-C
• rs397514436
• NM_001370658.1:c.132G>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001370658.1(BTD):​c.132G>C​(p.Glu44Asp) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.06
• Publications: 1 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 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, 0.964
• PP5: Variant 3-15635571-G-C is Pathogenic according to our data. Variant chr3-15635571-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 38574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.132G>C	p.Glu44Asp	missense_variant	Exon 2 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.132G>C	p.Glu44Asp	missense_variant	Exon 2 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Jan 13, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Biotinidase deficiency Pathogenic:1

Mar 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 64 of the BTD protein (p.Glu64Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761; Invitae). ClinVar contains an entry for this variant (Variation ID: 38574). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. This variant disrupts the p.Glu64 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 12359137), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;.;D;.;.;.;.;D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	.;D;D;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	.;.;M;.;.;.;.;.;.;.
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D;D;.;.;.;.;D;D;D;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;D;D;D;.
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.
Vest4		0.90, 0.92, 0.91
MutPred		0.83		.;.;Loss of sheet (P = 0.0357);.;Loss of sheet (P = 0.0357);.;.;.;.;.;
MVP		0.98
MPC		0.36
ClinPred		0.99	D
GERP RS		1.3
PromoterAI		0.053	Neutral
Varity_R		0.72
gMVP		0.96
Mutation Taster		=22/78	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: rs397514436; hg19: chr3-15677078;