3-15645027-C-T

Variant names:

• chr3-15645027-C-T
• rs35034250
• NM_001370658.1:c.1111C>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.1111C>T​(p.Pro371Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,614,166 control chromosomes in the GnomAD database, including 431 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P371L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (30 hom., cov: 32)
  • Exomes 𝑓: 0.022 (401 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.172
• Publications: 17 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 -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 biotinidase deficiency, Leigh syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031863153).
• BP6: Variant 3-15645027-C-T is Benign according to our data. Variant chr3-15645027-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.015 (2289/152286) while in subpopulation NFE AF = 0.0251 (1709/68018). AF 95% confidence interval is 0.0241. There are 30 homozygotes in GnomAd4. There are 1039 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.1111C>T	p.Pro371Ser	missense	Exon 4 of 4	NP_001357587.1	P43251-4
	BTD	NM_001281723.4		c.1111C>T	p.Pro371Ser	missense	Exon 4 of 4	NP_001268652.2	P43251-4
	BTD	NM_001281724.3		c.1111C>T	p.Pro371Ser	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.1111C>T	p.Pro371Ser	missense	Exon 4 of 4	ENSP00000495254.2	P43251-4
	BTD	ENST00000303498.10	TSL:1	c.1111C>T	p.Pro371Ser	missense	Exon 5 of 5	ENSP00000306477.6	P43251-4
	BTD	ENST00000427382.2	TSL:4	c.1111C>T	p.Pro371Ser	missense	Exon 4 of 4	ENSP00000397113.2	P43251-4

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2287 AN: 152168 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0139 AC: 3500 AN: 251428 AF XY: 0.0140

Gnomad AFR exome AF: 0.00474

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.0238

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0219 AC: 32039 AN: 1461880 Hom.: 401 Cov.: 31 AF XY: 0.0211 AC XY: 15346 AN XY: 727240

African (AFR) AF: 0.00391 AC: 131 AN: 33480

American (AMR) AF: 0.00635 AC: 284 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 114 AN: 26136

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

South Asian (SAS) AF: 0.00511 AC: 441 AN: 86256

European-Finnish (FIN) AF: 0.0112 AC: 596 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0263 AC: 29247 AN: 1112006

Other (OTH) AF: 0.0202 AC: 1218 AN: 60394

GnomAD4 genome AF: 0.0150 AC: 2289 AN: 152286 Hom.: 30 Cov.: 32 AF XY: 0.0140 AC XY: 1039 AN XY: 74456

African (AFR) AF: 0.00498 AC: 207 AN: 41572

American (AMR) AF: 0.0114 AC: 174 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4818

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0251 AC: 1709 AN: 68018

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0210 Hom.: 127

Bravo AF: 0.0147

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0241 AC: 207

ExAC AF: 0.0140 AC: 1698

EpiCase AF: 0.0239

EpiControl AF: 0.0204

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Biotinidase deficiency (4)
-	-	4	not provided (4)
-	-	4	not specified (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.7
DANN	Benign	0.43
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.17
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.16
Sift	Benign	0.26	T
Sift4G	Benign	0.45	T
Polyphen		0.0020	B
Vest4		0.064
MPC		0.072
ClinPred		0.0015	T
GERP RS		2.2
Varity_R		0.023
gMVP		0.50
Mutation Taster		=85/15	polymorphism (auto)

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: rs35034250; hg19: chr3-15686534; COSMIC: COSV107326670; COSMIC: COSV107326670;