rs77014096

chr21-36754206-T-Cchr21-36754206-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001352514.2(HLCS):c.*40A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,601,814 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (54 hom., cov: 33)
  • Exomes 𝑓: 0.027 (610 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-36754206-T-C is Benign according to our data. Variant chr21-36754206-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36754206-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.021 (3188/151622) while in subpopulation EAS AF= 0.0423 (216/5112). AF 95% confidence interval is 0.0376. There are 54 homozygotes in gnomad4. There are 1586 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.*40A>G		3_prime_UTR_variant	11/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.*40A>G		3_prime_UTR_variant	11/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3191 AN: 151504 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.00510

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0551

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0240

GnomAD3 exomes AF: 0.0270 AC: 6660 AN: 246708 Hom.: 89 AF XY: 0.0275 AC XY: 3682 AN XY: 133742

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0233

Gnomad ASJ exome AF: 0.0502

Gnomad EAS exome AF: 0.0423

Gnomad SAS exome AF: 0.0303

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0267 AC: 38734 AN: 1450192 Hom.: 610 Cov.: 28 AF XY: 0.0271 AC XY: 19577 AN XY: 721952

Gnomad4 AFR exome AF: 0.00475

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0504

Gnomad4 EAS exome AF: 0.0353

Gnomad4 SAS exome AF: 0.0314

Gnomad4 FIN exome AF: 0.0170

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0277

GnomAD4 genome AF: 0.0210 AC: 3188 AN: 151622 Hom.: 54 Cov.: 33 AF XY: 0.0214 AC XY: 1586 AN XY: 74048

Gnomad4 AFR AF: 0.00508

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.0551

Gnomad4 EAS AF: 0.0423

Gnomad4 SAS AF: 0.0268

Gnomad4 FIN AF: 0.0202

Gnomad4 NFE AF: 0.0261

Gnomad4 OTH AF: 0.0238

Alfa AF: 0.0267 Hom.: 17

Bravo AF: 0.0215

Asia WGS AF: 0.0240 AC: 85 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.49
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs77014096; hg19: chr21-38126507;