rs146011150

Variant names:

• chr3-15635507-A-G
• rs146011150
• NM_001370658.1:c.68A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001370658.1(BTD):​c.68A>G​(p.His23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,614,048 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: -0.380
• Publications: 4 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: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• 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 biotinidase deficiency, Leigh syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.041680098).
• BP6: Variant 3-15635507-A-G is Benign according to our data. Variant chr3-15635507-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38483.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370658.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	NM_001370658.1	MANE Select	c.68A>G	p.His23Arg	missense	Exon 2 of 4	NP_001357587.1	P43251-4
	BTD	NM_001281723.4		c.68A>G	p.His23Arg	missense	Exon 2 of 4	NP_001268652.2	P43251-4
	BTD	NM_001281724.3		c.68A>G	p.His23Arg	missense	Exon 4 of 6	NP_001268653.2	P43251-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	ENST00000643237.3	MANE Select	c.68A>G	p.His23Arg	missense	Exon 2 of 4	ENSP00000495254.2	P43251-4
	BTD	ENST00000303498.10	TSL:1	c.68A>G	p.His23Arg	missense	Exon 3 of 5	ENSP00000306477.6	P43251-4
	BTD	ENST00000427382.2	TSL:4	c.68A>G	p.His23Arg	missense	Exon 2 of 4	ENSP00000397113.2	P43251-4

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251424 AF XY: 0.000383

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000616

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000657 AC: 961 AN: 1461892 Hom.: 1 Cov.: 32 AF XY: 0.000635 AC XY: 462 AN XY: 727246

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000784 AC: 872 AN: 1112010

Other (OTH) AF: 0.000828 AC: 50 AN: 60396

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74336

African (AFR) AF: 0.000241 AC: 10 AN: 41436

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68016

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000558 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Biotinidase deficiency (5)
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	0.99
DANN	Benign	0.57
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.38
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.33
Sift	Benign	0.34	T
Sift4G	Benign	0.28	T
Polyphen		0.028	B
Vest4		0.098
MVP		0.68
MPC		0.086
ClinPred		0.020	T
GERP RS		-3.2
PromoterAI		-0.054	Neutral
Varity_R		0.028
gMVP		0.33
Mutation Taster		=91/9	polymorphism

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: rs146011150; hg19: chr3-15677014;