rs61732502

chr21-36937159-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001352514.2(HLCS):c.727G>A(p.Val243Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,104 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (258 hom., cov: 32)
  • Exomes 𝑓: 0.012 (406 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.37

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 (MetaRNN=0.0016494691).
• BP6: Variant 21-36937159-C-T is Benign according to our data. Variant chr21-36937159-C-T is described in ClinVar as [Benign]. Clinvar id is 137550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36937159-C-T is described in Lovd as [Benign]. Variant chr21-36937159-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.727G>A	p.Val243Ile	missense_variant	4/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.727G>A	p.Val243Ile	missense_variant	4/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6046 AN: 152110 Hom.: 259 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0353

Gnomad SAS AF: 0.0534

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0217 AC: 5457 AN: 251442 Hom.: 183 AF XY: 0.0212 AC XY: 2879 AN XY: 135900

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00960

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.0383

Gnomad SAS exome AF: 0.0478

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.00573

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0117 AC: 17058 AN: 1461876 Hom.: 406 Cov.: 34 AF XY: 0.0125 AC XY: 9104 AN XY: 727244

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0100

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.0380

Gnomad4 SAS exome AF: 0.0466

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.00483

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0398 AC: 6053 AN: 152228 Hom.: 258 Cov.: 32 AF XY: 0.0403 AC XY: 2997 AN XY: 74426

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0355

Gnomad4 SAS AF: 0.0533

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.00591

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0112 Hom.: 86

Bravo AF: 0.0410

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.107 AC: 471

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.0246 AC: 2993

Asia WGS AF: 0.0470 AC: 163 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00474

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Holocarboxylase synthetase deficiency Benign:3

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.0030
Dann	Benign	0.57
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.15	T;.;.
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.014
MPC		0.099
ClinPred		0.0078	T
GERP RS		-11
Varity_R		0.024
gMVP		0.062

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61732502; hg19: chr21-38309459; COSMIC: COSV100357923; COSMIC: COSV100357923;