rs1065758

Positions:

• chr21-36936611-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001352514.2(HLCS):​c.1275C>T​(p.Ser425=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,614,060 control chromosomes in the GnomAD database, including 19,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1279 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18220 hom.)
• Consequence: HLCS NM_001352514.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.689

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-36936611-G-A is Benign according to our data. Variant chr21-36936611-G-A is described in ClinVar as [Benign]. Clinvar id is 92916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36936611-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.689 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1275C>T	p.Ser425=	synonymous_variant	4/11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.1275C>T	p.Ser425=	synonymous_variant	4/11		NM_001352514.2	ENSP00000502087	P4

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17769 AN: 152086 Hom.: 1280 Cov.: 32

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0846

Gnomad ASJ AF: 0.0994

Gnomad EAS AF: 0.0486

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.119 AC: 30006 AN: 251134 Hom.: 2189 AF XY: 0.121 AC XY: 16462 AN XY: 135748

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.0632

Gnomad ASJ exome AF: 0.0982

Gnomad EAS exome AF: 0.0480

Gnomad SAS exome AF: 0.0647

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.153 AC: 223330 AN: 1461856 Hom.: 18220 Cov.: 35 AF XY: 0.151 AC XY: 109543 AN XY: 727230

Gnomad4 AFR exome AF: 0.0429

Gnomad4 AMR exome AF: 0.0663

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.0511

Gnomad4 SAS exome AF: 0.0670

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.117 AC: 17763 AN: 152204 Hom.: 1279 Cov.: 32 AF XY: 0.114 AC XY: 8495 AN XY: 74428

Gnomad4 AFR AF: 0.0472

Gnomad4 AMR AF: 0.0844

Gnomad4 ASJ AF: 0.0994

Gnomad4 EAS AF: 0.0487

Gnomad4 SAS AF: 0.0618

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.112

Alfa AF: 0.150 Hom.: 3530

Bravo AF: 0.108

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.165

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.89
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1065758; hg19: chr21-38308911; COSMIC: COSV60793855; COSMIC: COSV60793855;