21-36930243-CA-C

Variant names:

• chr21-36930243-CA-C
• rs140568778
• NM_001352514.2:c.1620+7delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001352514.2(HLCS):​c.1620+7delT 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1620+7delT		splice_region_variant, intron_variant	Intron 5 of 10	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.1620+7delT		splice_region_variant, intron_variant	Intron 5 of 10		NM_001352514.2	ENSP00000502087.2

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

GnomAD2 exomes AF: 0.134 AC: 33730 AN: 251328 AF XY: 0.138

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 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 AC: 953 AN: 33470

Gnomad4 AMR exome AF: 0.0789 AC: 3530 AN: 44722

Gnomad4 ASJ exome AF: 0.182 AC: 4766 AN: 26134

Gnomad4 EAS exome AF: 0.00154 AC: 61 AN: 39698

Gnomad4 SAS exome AF: 0.0901 AC: 7775 AN: 86248

Gnomad4 FIN exome AF: 0.179 AC: 9576 AN: 53408

Gnomad4 NFE exome AF: 0.194 AC: 215260 AN: 1111324

Gnomad4 Remaining exome AF: 0.158 AC: 9566 AN: 60366

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 AC: 0.0353001 AN: 0.0353001

Gnomad4 AMR AF: 0.0992 AC: 0.0991633 AN: 0.0991633

Gnomad4 ASJ AF: 0.190 AC: 0.189914 AN: 0.189914

Gnomad4 EAS AF: 0.00212 AC: 0.00212273 AN: 0.00212273

Gnomad4 SAS AF: 0.0867 AC: 0.086686 AN: 0.086686

Gnomad4 FIN AF: 0.182 AC: 0.182075 AN: 0.182075

Gnomad4 NFE AF: 0.190 AC: 0.189524 AN: 0.189524

Gnomad4 OTH AF: 0.130 AC: 0.130332 AN: 0.130332

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

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Holocarboxylase synthetase deficiency Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs140568778; hg19: chr21-38302543;