3-15635615-G-C

Variant names:

• chr3-15635615-G-C
• rs397514343
• NM_001370658.1:c.176G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001370658.1(BTD):​c.176G>C​(p.Arg59Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.95

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-15635614-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.176G>C	p.Arg59Pro	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.176G>C	p.Arg59Pro	missense_variant	Exon 2 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;.;D;.;.;.;.;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.55	.;T;T;.;T;.;T;T;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.3	.;.;M;.;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.0	D;D;.;.;.;.;D;D;D;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;T;.;.;.;.;T;T;T;.
Sift4G	Benign	0.16	.;T;.;.;.;.;T;T;T;.
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.
Vest4		0.90, 0.90, 0.87
MutPred		0.59		.;.;Gain of catalytic residue at R79 (P = 0.0906);.;Gain of catalytic residue at R79 (P = 0.0906);.;.;.;.;.;
MVP		0.97
MPC		0.50
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.80
gMVP		0.96

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: rs397514343; hg19: chr3-15677122;