3-15601536-A-G

Variant names:

• chr3-15601536-A-G
• rs2019160
• NM_012260.4:c.-73T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012260.4(HACL1):​c.-73T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.954 in 1,606,886 control chromosomes in the GnomAD database, including 731,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70512 hom., cov: 32)
  • Exomes 𝑓: 0.95 (660996 hom.)
• Consequence: HACL1 NM_012260.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05
• Publications: 10 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=-0.81).
• BP6: Variant 3-15601536-A-G is Benign according to our data. Variant chr3-15601536-A-G is described in ClinVar as Benign. ClinVar VariationId is 1266847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.984 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012260.4. 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
	HACL1	NM_012260.4	MANE Select	c.-73T>C		5_prime_UTR	Exon 1 of 17	NP_036392.2	Q9UJ83-1
	HACL1	NM_001284413.2		c.-73T>C		5_prime_UTR	Exon 1 of 16	NP_001271342.1	Q9UJ83-2
	BTD	NM_001407365.1		c.-128A>G		5_prime_UTR	Exon 1 of 4	NP_001394294.1	P43251-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACL1	ENST00000321169.10	TSL:1 MANE Select	c.-73T>C		5_prime_UTR	Exon 1 of 17	ENSP00000323811.5	Q9UJ83-1
	HACL1	ENST00000383779.8	TSL:1	n.-73T>C		non_coding_transcript_exon	Exon 1 of 15	ENSP00000373289.4	Q7Z773
	HACL1	ENST00000383779.8	TSL:1	n.-73T>C		5_prime_UTR	Exon 1 of 15	ENSP00000373289.4	Q7Z773

Frequencies

GnomAD3 genomes AF: 0.962 AC: 146394 AN: 152220 Hom.: 70452 Cov.: 32

Gnomad AFR AF: 0.992

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.960

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.949

Gnomad OTH AF: 0.953

GnomAD2 exomes AF: 0.958 AC: 235112 AN: 245494 AF XY: 0.956

Gnomad AFR exome AF: 0.991

Gnomad AMR exome AF: 0.969

Gnomad ASJ exome AF: 0.946

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.927

Gnomad NFE exome AF: 0.948

Gnomad OTH exome AF: 0.949

GnomAD4 exome AF: 0.953 AC: 1386505 AN: 1454548 Hom.: 660996 Cov.: 128 AF XY: 0.953 AC XY: 689871 AN XY: 723922

African (AFR) AF: 0.993 AC: 33240 AN: 33476

American (AMR) AF: 0.969 AC: 43268 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.944 AC: 24680 AN: 26134

East Asian (EAS) AF: 0.994 AC: 39450 AN: 39696

South Asian (SAS) AF: 0.960 AC: 82722 AN: 86210

European-Finnish (FIN) AF: 0.925 AC: 42949 AN: 46418

Middle Eastern (MID) AF: 0.953 AC: 5495 AN: 5766

European-Non Finnish (NFE) AF: 0.951 AC: 1057030 AN: 1111838

Other (OTH) AF: 0.956 AC: 57671 AN: 60336

GnomAD4 genome AF: 0.962 AC: 146514 AN: 152338 Hom.: 70512 Cov.: 32 AF XY: 0.962 AC XY: 71661 AN XY: 74482

African (AFR) AF: 0.992 AC: 41222 AN: 41572

American (AMR) AF: 0.960 AC: 14692 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 3289 AN: 3470

East Asian (EAS) AF: 0.994 AC: 5139 AN: 5170

South Asian (SAS) AF: 0.962 AC: 4645 AN: 4826

European-Finnish (FIN) AF: 0.927 AC: 9851 AN: 10628

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.949 AC: 64564 AN: 68042

Other (OTH) AF: 0.954 AC: 2018 AN: 2116

Alfa AF: 0.959 Hom.: 14357

Bravo AF: 0.965

Asia WGS AF: 0.970 AC: 3375 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	-0.81
CADD	Benign	1.3
DANN	Benign	0.46
PhyloP100		-1.0
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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: rs2019160; hg19: chr3-15643043;