rs397514399

Variant names:

• chr3-15644952-T-C
• rs397514399
• NM_001370658.1:c.1036T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001370658.1(BTD):​c.1036T>C​(p.Ser346Pro) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S346S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.505
• 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: Uncertain_significance. The variant received 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15010095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1036T>C	p.Ser346Pro	missense_variant	Exon 4 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.1036T>C	p.Ser346Pro	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.000597 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;T;.;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.51	.;T;T;.;.;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	2.0	.;.;M;.;.;.;.
PhyloP100		-0.51
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.36	.;N;.;.;.;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.082	.;T;.;.;.;T;T
Sift4G	Benign	0.14	.;T;.;.;.;T;T
Polyphen		0.28	.;.;B;.;.;.;.
Vest4		0.56, 0.68, 0.48
MutPred		0.45		.;.;Loss of sheet (P = 0.0181);.;.;.;.;
MVP		0.82
MPC		0.12
ClinPred		0.077	T
GERP RS		0.28
Varity_R		0.080
gMVP		0.81
Mutation Taster		=3/97	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: rs397514399; hg19: chr3-15686459;