rs397514354

Variant names:

• chr3-15641962-A-G
• rs397514354
• NM_001370658.1:c.304A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001370658.1(BTD):​c.304A>G​(p.Arg102Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 4.89
• 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: Pathogenic. The variant received 10 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, 3 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.991
• PP5: Variant 3-15641962-A-G is Pathogenic according to our data. Variant chr3-15641962-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25001.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.304A>G	p.Arg102Gly	missense_variant	Exon 3 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.304A>G	p.Arg102Gly	missense_variant	Exon 3 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111912

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Pathogenic:1 Uncertain:1

Apr 02, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Dec 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BTD c.304A>G (p.Arg102Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.304A>G has been reported in the literature in individuals affected with Biotinidase Deficiency (e.g. Norrgard_1999, Wiltink_2016, Carvalho_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10400129, 27329734, 31801038). ClinVar contains an entry for this variant (Variation ID: 25001). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Apr 27, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BTD c.364A>G; p.Arg122Gly variant (rs397514354) is reported in the literature in an individual who was compound heterozygous and affected with profound biotinidase deficiency (Norrgard 1999). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 122 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Arg122Gly variant is uncertain at this time. REFERENCES Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;D;.;.;.;.;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;D;D;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;.;.;.;.
PhyloP100		4.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.7	.;D;.;.;.;.;D;D;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	.;D;.;.;.;.;D;D;D;.
Sift4G	Uncertain	0.0050	.;D;.;.;.;.;D;D;D;.
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.
Vest4		0.94, 0.94, 0.94
MutPred		0.95		.;.;Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);.;.;.;.;.;
MVP		0.99
MPC		0.47
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.95
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397514354; hg19: chr3-15683469;