rs13078881

Variant names:

• chr3-15645186-G-C
• rs13078881
• NM_001370658.1:c.1270G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-15645186-G-C
• chr3-15645186-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PS3 PM1 PM5 PP2 PP5 BP4

The NM_001370658.1(BTD):​c.1270G>C​(p.Asp424His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0381 in 1,614,178 control chromosomes in the GnomAD database, including 1,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000221176: In vitro functional studies support an impact on protein function (Borsatto 2019 PMID:31337602, Liu 2018 PMID:29359854)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D424Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.029 (95 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1213 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:49 U:3 O:3
• Conservation: PhyloP100: 3.24
• Publications: 116 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_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000221176: In vitro functional studies support an impact on protein function (Borsatto 2019 PMID: 31337602, Liu 2018 PMID: 29359854).; SCV001363363: Multiple publications report experimental evidence evaluating an impact on protein function. One study reported that this variant results in decreased protein expression but does not alter the activity of BTD enzyme (Liu_2018). Another study reports 46% of wild-type activity in cell homogenates but not in culture medium suggestive of an effect on enzyme lability rather than enzyme activity (Borsatto_2019).; SCV002061253: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 31208052; 31337602) - PS3_moderate."; SCV002754532: Functional studies have shown that this variant alters BTD protein function (PMID: 29359854, 31337602) (PS3_Moderate).; SCV002766823: "This variant has moderate functional evidence supporting abnormal protein function. Western blot and enzyme activity assays for this variant have been variable between individuals but it is generally accepted that this variant reduces enzyme activity by around 50% (PMID: 31337602)."; SCV002818282: PS3; SCV003841936: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10206677, 9654207)."; SCV004232355: Well-established in vitro functional studies and patient assays of the p.Asp424His variant demonstrate reduced enzymatic activity that is sufficient to be disease-causing (Liu et al., 2018; Swango et al., 1998).; SCV005417344: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000888008: Assessment of experimental evidence suggests this variant results in reduced BTD enzyme activity (PMID: 10206677 (1998), 12227467 (2002)).; SCV001551792: Liu et al. (2018) recently found that the D444H variant results in a decrease in protein expression with no loss of enzyme activity (Liu_2018_PMID: 29359854).; SCV002692535: "In vitro studies showed slightly reduced but not complete loss of biotinidase activity in HEK293 cells (Borsatto, 2019)."
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001370658.1
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-15645186-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3588707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP5: Variant 3-15645186-G-C is Pathogenic according to our data. Variant chr3-15645186-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1900.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01670149). . Strength limited to SUPPORTING due to the PP5.

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.1270G>C	p.Asp424His	missense	Exon 4 of 4	NP_001357587.1	P43251-4
	BTD	NM_001281723.4		c.1270G>C	p.Asp424His	missense	Exon 4 of 4	NP_001268652.2	P43251-4
	BTD	NM_001281724.3		c.1270G>C	p.Asp424His	missense	Exon 6 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.1270G>C	p.Asp424His	missense	Exon 4 of 4	ENSP00000495254.2	P43251-4
	BTD	ENST00000303498.10	TSL:1	c.1270G>C	p.Asp424His	missense	Exon 5 of 5	ENSP00000306477.6	P43251-4
	BTD	ENST00000427382.2	TSL:4	c.1270G>C	p.Asp424His	missense	Exon 4 of 4	ENSP00000397113.2	P43251-4

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4481 AN: 152172 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.00818

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.0553

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0403

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0323 AC: 8109 AN: 251430 AF XY: 0.0337

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0559

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0306

GnomAD4 exome AF: 0.0390 AC: 57018 AN: 1461888 Hom.: 1213 Cov.: 31 AF XY: 0.0389 AC XY: 28319 AN XY: 727244

African (AFR) AF: 0.00547 AC: 183 AN: 33480

American (AMR) AF: 0.0189 AC: 847 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 860 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0371 AC: 3201 AN: 86258

European-Finnish (FIN) AF: 0.0525 AC: 2802 AN: 53418

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5768

European-Non Finnish (NFE) AF: 0.0420 AC: 46676 AN: 1112008

Other (OTH) AF: 0.0385 AC: 2325 AN: 60396

GnomAD4 genome AF: 0.0294 AC: 4479 AN: 152290 Hom.: 95 Cov.: 32 AF XY: 0.0305 AC XY: 2272 AN XY: 74476

African (AFR) AF: 0.00813 AC: 338 AN: 41564

American (AMR) AF: 0.0287 AC: 439 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0377 AC: 182 AN: 4822

European-Finnish (FIN) AF: 0.0553 AC: 587 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0403 AC: 2743 AN: 68016

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0352 Hom.: 88

Bravo AF: 0.0256

TwinsUK AF: 0.0391 AC: 145

ALSPAC AF: 0.0441 AC: 170

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.0415 AC: 357

ExAC AF: 0.0317 AC: 3844

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0398

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
36	3	-	Biotinidase deficiency (42)
10	-	-	not provided (10)
1	-	-	BTD-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Possible mitochondrial disorder - nuclear genes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	0.0067	T
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.2
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.15
MPC		0.11
ClinPred		0.087	T
GERP RS		3.8
Varity_R		0.32
gMVP		0.82
Mutation Taster		=62/38	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: rs13078881; hg19: chr3-15686693;