21-36751622-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001352514.2(HLCS):c.*2624G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00737 in 152,512 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (3 hom., cov: 33)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.662

Genes affected

HLCS (HGNC:4976): (holocarboxylase synthetase) This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 21-36751622-C-T is Benign according to our data. Variant chr21-36751622-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 339919.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00736 (1122/152366) while in subpopulation NFE AF= 0.0128 (869/68032). AF 95% confidence interval is 0.0121. There are 3 homozygotes in gnomad4. There are 511 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.*2624G>A		3_prime_UTR_variant	11/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.*2624G>A		3_prime_UTR_variant	11/11		NM_001352514.2	P4
HLCS	ENST00000336648.8	c.*2624G>A		3_prime_UTR_variant	12/12	1		A1
HLCS	ENST00000399120.5	c.*2624G>A		3_prime_UTR_variant	12/12	1		A1
HLCS	ENST00000612277.4	c.*2624G>A		3_prime_UTR_variant	12/12	5		A1

Frequencies

GnomAD3 genomes AF: 0.00737 AC: 1122 AN: 152248 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00525

GnomAD4 exome AF: 0.0137 AC: 2 AN: 146 Hom.: 0 Cov.: 0 AF XY: 0.00806 AC XY: 1 AN XY: 124

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00736 AC: 1122 AN: 152366 Hom.: 3 Cov.: 33 AF XY: 0.00686 AC XY: 511 AN XY: 74516

Gnomad4 AFR AF: 0.00305

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0114 Hom.: 2

Bravo AF: 0.00717

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.42
Dann	Benign	0.51

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: rs73210780; hg19: chr21-38123923;