rs114092911

Variant names:

• chr3-15635581-A-G
• rs114092911
• NM_001370658.1:c.142A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-15635581-A-G
• chr3-15635581-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 3P and 17B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_001370658.1(BTD):​c.142A>G​(p.Ile48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,192 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (8 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.728
• Publications: 0 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: Benign. The variant received -14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001370658.1
• 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=0.0063790977).
• BP6: Variant 3-15635581-A-G is Benign according to our data. Variant chr3-15635581-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 528480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00659 (1004/152298) while in subpopulation AFR AF = 0.0229 (953/41568). AF 95% confidence interval is 0.0217. There are 9 homozygotes in GnomAd4. There are 475 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.142A>G	p.Ile48Val	missense	Exon 2 of 4	NP_001357587.1
	BTD	NM_001281723.4		c.142A>G	p.Ile48Val	missense	Exon 2 of 4	NP_001268652.2
	BTD	NM_001281724.3		c.142A>G	p.Ile48Val	missense	Exon 4 of 6	NP_001268653.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	ENST00000643237.3	MANE Select	c.142A>G	p.Ile48Val	missense	Exon 2 of 4	ENSP00000495254.2
	BTD	ENST00000303498.10	TSL:1	c.142A>G	p.Ile48Val	missense	Exon 3 of 5	ENSP00000306477.6
	BTD	ENST00000427382.2	TSL:4	c.142A>G	p.Ile48Val	missense	Exon 2 of 4	ENSP00000397113.2

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1002 AN: 152180 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00147 AC: 370 AN: 251438 AF XY: 0.00111

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000621 AC: 908 AN: 1461894 Hom.: 8 Cov.: 32 AF XY: 0.000502 AC XY: 365 AN XY: 727248

African (AFR) AF: 0.0225 AC: 754 AN: 33480

American (AMR) AF: 0.00107 AC: 48 AN: 44724

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

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

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

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112012

Other (OTH) AF: 0.00136 AC: 82 AN: 60396

GnomAD4 genome AF: 0.00659 AC: 1004 AN: 152298 Hom.: 9 Cov.: 33 AF XY: 0.00638 AC XY: 475 AN XY: 74470

African (AFR) AF: 0.0229 AC: 953 AN: 41568

American (AMR) AF: 0.00229 AC: 35 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00120 Hom.: 4

Bravo AF: 0.00737

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00191 AC: 232

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Biotinidase deficiency (3)
-	-	3	not provided (3)
-	-	1	BTD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.13
DANN	Benign	0.37
DEOGEN2	Benign	0.34	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.73
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.17
Sift	Benign	0.54	T
Sift4G	Benign	0.36	T
Polyphen		0.0080	B
Vest4		0.093
MVP		0.78
MPC		0.062
ClinPred		0.0011	T
GERP RS		-3.9
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.56
Mutation Taster		=100/0	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: rs114092911; hg19: chr3-15677088;