3-15601668-G-A

Position:

• chr3-15601668-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001407365.1(BTD):​c.-17+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0928 in 1,553,726 control chromosomes in the GnomAD database, including 8,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1012 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7878 hom.)
• Consequence: BTD NM_001407365.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.96

Genes affected

HACL1 (HGNC:17856): (2-hydroxyacyl-CoA lyase 1) Enables several functions, including 2-hydroxy-3-methylhexadecanoyl-CoA lyase activity; ATP binding activity; and cation binding activity. Involved in fatty acid alpha-oxidation; phytanic acid metabolic process; and protein targeting to peroxisome. Located in nucleoplasm and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-15601668-G-A is Benign according to our data. Variant chr3-15601668-G-A is described in ClinVar as [Benign]. Clinvar id is 1221031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001407365.1	c.-17+21G>A		intron_variant			NP_001394294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HACL1	ENST00000628377.2	c.-205C>T		5_prime_UTR_premature_start_codon_gain_variant	1/16	5		ENSP00000486684.1
BTD	ENST00000449107	c.-119G>A		5_prime_UTR_variant	1/4	2		ENSP00000388212.2
HACL1	ENST00000628377.2	c.-205C>T		5_prime_UTR_variant	1/16	5		ENSP00000486684.1
BTD	ENST00000427382.2	c.-17+21G>A		intron_variant		4		ENSP00000397113.2

Frequencies

GnomAD3 genomes AF: 0.0999 AC: 15199 AN: 152148 Hom.: 1011 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0614

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0786

Gnomad OTH AF: 0.0961

GnomAD4 exome AF: 0.0920 AC: 128915 AN: 1401460 Hom.: 7878 Cov.: 35 AF XY: 0.0935 AC XY: 64646 AN XY: 691646

Gnomad4 AFR exome AF: 0.0965

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.0554

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.0570

Gnomad4 NFE exome AF: 0.0786

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.0998 AC: 15202 AN: 152266 Hom.: 1012 Cov.: 32 AF XY: 0.101 AC XY: 7533 AN XY: 74464

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0614

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.0527

Gnomad4 NFE AF: 0.0786

Gnomad4 OTH AF: 0.0960

Alfa AF: 0.0818 Hom.: 1094

Bravo AF: 0.106

Asia WGS AF: 0.234 AC: 810 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.59
DANN	Benign	0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs2279841; hg19: chr3-15643175; COSMIC: COSV57729171; COSMIC: COSV57729171;