rs34885143

Variant names:

• chr3-15635512-G-A
• rs34885143
• NM_001370658.1:c.73G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-15635512-G-A
• chr3-15635512-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6 BS1 BS2_Supporting

The NM_001370658.1(BTD):​c.73G>A​(p.Gly25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,614,134 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.010 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (156 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: -0.0140
• Publications: 11 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: Benign. The variant received -9 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 Leigh syndrome, biotinidase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005297005).
• BP6: Variant 3-15635512-G-A is Benign according to our data. Variant chr3-15635512-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 24973.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.014 (20455/1461890) while in subpopulation NFE AF = 0.0161 (17863/1112008). AF 95% confidence interval is 0.0159. There are 156 homozygotes in GnomAdExome4. There are 9951 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.73G>A	p.Gly25Arg	missense	Exon 2 of 4	NP_001357587.1	P43251-4
	BTD	NM_001281723.4		c.73G>A	p.Gly25Arg	missense	Exon 2 of 4	NP_001268652.2	P43251-4
	BTD	NM_001281724.3		c.73G>A	p.Gly25Arg	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.73G>A	p.Gly25Arg	missense	Exon 2 of 4	ENSP00000495254.2	P43251-4
	BTD	ENST00000303498.10	TSL:1	c.73G>A	p.Gly25Arg	missense	Exon 3 of 5	ENSP00000306477.6	P43251-4
	BTD	ENST00000427382.2	TSL:4	c.73G>A	p.Gly25Arg	missense	Exon 2 of 4	ENSP00000397113.2	P43251-4

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1534 AN: 152126 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.0102 AC: 2560 AN: 251422 AF XY: 0.0101

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0240

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0140 AC: 20455 AN: 1461890 Hom.: 156 Cov.: 32 AF XY: 0.0137 AC XY: 9951 AN XY: 727244

African (AFR) AF: 0.00206 AC: 69 AN: 33480

American (AMR) AF: 0.00373 AC: 167 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00435 AC: 375 AN: 86258

European-Finnish (FIN) AF: 0.0246 AC: 1316 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0161 AC: 17863 AN: 1112008

Other (OTH) AF: 0.0106 AC: 639 AN: 60396

GnomAD4 genome AF: 0.0101 AC: 1535 AN: 152244 Hom.: 13 Cov.: 32 AF XY: 0.00997 AC XY: 742 AN XY: 74442

African (AFR) AF: 0.00233 AC: 97 AN: 41550

American (AMR) AF: 0.00438 AC: 67 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1052 AN: 68008

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.0135 Hom.: 50

Bravo AF: 0.00868

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.00995 AC: 1208

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0122

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Biotinidase deficiency (6)
-	1	3	not provided (4)
-	1	1	not specified (2)
-	-	1	BTD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	1.6
DANN	Benign	0.81
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.014
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.43
Sift	Benign	0.11	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.74		Gain of phosphorylation at S48 (P = 0.0901)
MPC		0.084
ClinPred		0.013	T
GERP RS		-0.69
PromoterAI		0.015	Neutral
Varity_R		0.032
gMVP		0.36
Mutation Taster		=81/19	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: rs34885143; hg19: chr3-15677019; COSMIC: COSV108147139; COSMIC: COSV108147139;