rs796051976

chr21-36930243-CA-Cchr21-36930243-C-CA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001352514.2(HLCS):c.1620+7del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,368 control chromosomes in the GnomAD database, including 25,229 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1587 hom., cov: 30)
  • Exomes 𝑓: 0.17 (23642 hom.)
• Consequence: HLCS NM_001352514.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.51

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 -16 ACMG points.

• BP6: Variant 21-36930243-CA-C is Benign according to our data. Variant chr21-36930243-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 92915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36930243-CA-C is described in Lovd as [Benign]. Variant chr21-36930243-CA-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.1620+7del		splice_region_variant, intron_variant		ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.1620+7del		splice_region_variant, intron_variant			NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19232 AN: 152114 Hom.: 1588 Cov.: 30

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0994

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0866

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.134 AC: 33730 AN: 251328 Hom.: 2875 AF XY: 0.138 AC XY: 18686 AN XY: 135840

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.00359

Gnomad SAS exome AF: 0.0867

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.173 AC: 252293 AN: 1461136 Hom.: 23642 Cov.: 30 AF XY: 0.171 AC XY: 124155 AN XY: 726882

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.0789

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.00154

Gnomad4 SAS exome AF: 0.0901

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.126 AC: 19227 AN: 152232 Hom.: 1587 Cov.: 30 AF XY: 0.123 AC XY: 9184 AN XY: 74432

Gnomad4 AFR AF: 0.0353

Gnomad4 AMR AF: 0.0992

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0867

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.130

Alfa AF: 0.164 Hom.: 394

Bravo AF: 0.118

Asia WGS AF: 0.0610 AC: 212 AN: 3478

EpiCase AF: 0.187

EpiControl AF: 0.189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2013	- -

Holocarboxylase synthetase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs140568778; hg19: chr21-38302543;