3-15601668-G-A

Variant names:

• chr3-15601668-G-A
• rs2279841
• ENST00000900333.1:c.-205C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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]

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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407365.1. 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_001407365.1		c.-17+21G>A		intron	N/A	NP_001394294.1	P43251-4
	HACL1	NM_012260.4	MANE Select	c.-205C>T		upstream_gene	N/A	NP_036392.2	Q9UJ83-1
	BTD	NM_001370658.1	MANE Select	c.-243G>A		upstream_gene	N/A	NP_001357587.1	P43251-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACL1	ENST00000900333.1		c.-205C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000570392.1
	HACL1	ENST00000900332.1		c.-205C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000570391.1
	HACL1	ENST00000936950.1		c.-205C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000607009.1

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

African (AFR) AF: 0.0965 AC: 3078 AN: 31880

American (AMR) AF: 0.165 AC: 5916 AN: 35824

Ashkenazi Jewish (ASJ) AF: 0.0554 AC: 1395 AN: 25192

East Asian (EAS) AF: 0.340 AC: 12266 AN: 36028

South Asian (SAS) AF: 0.154 AC: 12299 AN: 80036

European-Finnish (FIN) AF: 0.0570 AC: 2753 AN: 48282

Middle Eastern (MID) AF: 0.0397 AC: 226 AN: 5698

European-Non Finnish (NFE) AF: 0.0786 AC: 84917 AN: 1080358

Other (OTH) AF: 0.104 AC: 6065 AN: 58162

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

African (AFR) AF: 0.104 AC: 4312 AN: 41550

American (AMR) AF: 0.113 AC: 1724 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0614 AC: 213 AN: 3468

East Asian (EAS) AF: 0.373 AC: 1929 AN: 5176

South Asian (SAS) AF: 0.179 AC: 863 AN: 4830

European-Finnish (FIN) AF: 0.0527 AC: 559 AN: 10610

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0786 AC: 5345 AN: 68020

Other (OTH) AF: 0.0960 AC: 203 AN: 2114

Alfa AF: 0.0860 Hom.: 1955

Bravo AF: 0.106

Asia WGS AF: 0.234 AC: 810 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.59
DANN	Benign	0.90
PhyloP100		-3.0
PromoterAI		0.042	Neutral
Mutation Taster		=300/0	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: rs2279841; hg19: chr3-15643175; COSMIC: COSV57729171; COSMIC: COSV57729171;