rs397514432

Variant names:

• chr3-15645483-G-A
• rs397514432
• NM_001370658.1:c.1567G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-15645483-G-A
• chr3-15645483-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_001370658.1(BTD):​c.1567G>A​(p.Asp523Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,453,252 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D523V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.25
• Publications: 2 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-15645485-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1567G>A	p.Asp523Asn	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.1567G>A	p.Asp523Asn	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 236824 AF XY: 0.00000770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453252 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723154

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;D;.;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	.;T;T;.;.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.1	.;.;M;.;.;.;.
PhyloP100		5.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;.;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.039	.;D;.;.;.;D;D
Sift4G	Pathogenic	0.0	.;D;.;.;.;D;D
Polyphen		0.51	.;.;P;.;.;.;.
Vest4		0.39, 0.37, 0.32
MutPred		0.75		.;.;Gain of MoRF binding (P = 0.0479);.;.;.;.;
MVP		0.81
MPC		0.13
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.32
gMVP		0.80
Mutation Taster		=50/50

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: rs397514432; hg19: chr3-15686990;