NM_001370658.1:c.820A>G

Variant names:

• chr3-15644736-A-G
• rs35976361
• NM_001370658.1:c.820A>G

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.820A>G​(p.Ile274Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,614,190 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0220
• Publications: 8 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: G2P, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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=0.006632507).
• BP6: Variant 3-15644736-A-G is Benign according to our data. Variant chr3-15644736-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 25047.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 = 0.0109 (1663/152296) while in subpopulation AFR AF = 0.0384 (1594/41558). AF 95% confidence interval is 0.0368. There are 40 homozygotes in GnomAd4. There are 794 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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.820A>G	p.Ile274Val	missense	Exon 4 of 4	NP_001357587.1
	BTD	NM_001281723.4		c.820A>G	p.Ile274Val	missense	Exon 4 of 4	NP_001268652.2
	BTD	NM_001281724.3		c.820A>G	p.Ile274Val	missense	Exon 6 of 6	NP_001268653.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	ENST00000643237.3	MANE Select	c.820A>G	p.Ile274Val	missense	Exon 4 of 4	ENSP00000495254.2
	BTD	ENST00000303498.10	TSL:1	c.820A>G	p.Ile274Val	missense	Exon 5 of 5	ENSP00000306477.6
	BTD	ENST00000427382.2	TSL:4	c.820A>G	p.Ile274Val	missense	Exon 4 of 4	ENSP00000397113.2

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1654 AN: 152178 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00324 AC: 814 AN: 251404 AF XY: 0.00230

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00123 AC: 1796 AN: 1461894 Hom.: 34 Cov.: 31 AF XY: 0.00105 AC XY: 767 AN XY: 727248

African (AFR) AF: 0.0422 AC: 1412 AN: 33480

American (AMR) AF: 0.00320 AC: 143 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: 0.000209 AC: 18 AN: 86258

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

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1112012

Other (OTH) AF: 0.00248 AC: 150 AN: 60396

GnomAD4 genome AF: 0.0109 AC: 1663 AN: 152296 Hom.: 40 Cov.: 32 AF XY: 0.0107 AC XY: 794 AN XY: 74468

African (AFR) AF: 0.0384 AC: 1594 AN: 41558

American (AMR) AF: 0.00359 AC: 55 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00470 Hom.: 29

Bravo AF: 0.0129

ESP6500AA AF: 0.0395 AC: 174

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00396 AC: 481

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Biotinidase deficiency (7)
-	-	4	not provided (4)
-	-	1	BTD-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.018
DANN	Benign	0.21
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.022
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.64	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.049
MVP		0.50
MPC		0.061
ClinPred		0.0019	T
GERP RS		-4.3
Varity_R		0.016
gMVP		0.67
Mutation Taster		=83/17	disease causing (ClinVar)

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: rs35976361; hg19: chr3-15686243; COSMIC: COSV99068531; COSMIC: COSV99068531;