rs149736764

Positions:

• chr21-36765020-C-T
• chr21-36765020-C-G

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.2113G>A​(p.Glu705Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00187 in 1,614,196 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (13 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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 (MetaRNN=0.0096511245).
• BP6: Variant 21-36765020-C-T is Benign according to our data. Variant chr21-36765020-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 203754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36765020-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00304 (463/152316) while in subpopulation AFR AF= 0.00519 (216/41582). AF 95% confidence interval is 0.00463. There are 2 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.2113G>A	p.Glu705Lys	missense_variant	8/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.2113G>A	p.Glu705Lys	missense_variant	8/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 463 AN: 152198 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00275 AC: 691 AN: 251480 Hom.: 6 AF XY: 0.00252 AC XY: 343 AN XY: 135916

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00586

GnomAD4 exome AF: 0.00175 AC: 2555 AN: 1461880 Hom.: 13 Cov.: 32 AF XY: 0.00172 AC XY: 1251 AN XY: 727244

Gnomad4 AFR exome AF: 0.00565

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.00304 AC: 463 AN: 152316 Hom.: 2 Cov.: 33 AF XY: 0.00294 AC XY: 219 AN XY: 74466

Gnomad4 AFR AF: 0.00519

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00255 Hom.: 8

Bravo AF: 0.00387

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00237 AC: 288

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 02, 2016	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene assocaited with multiple carboxylase deficiency/ holocarboxylase synthetase deficiency - Affected infants often have difficulty feeding, breathing problems, a skin rash, hair loss (alopecia), and a lack of energy (lethargy).2 homo Europeans. Frequency of this variant is too high for the disorder ( estimated to affect 1 in 87,000 people) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2018	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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Uncertain	0.43	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.76	T;.;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.15	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.21	B;B;B
Vest4		0.26
MVP		0.76
MPC		0.31
ClinPred		0.014	T
GERP RS		1.8
Varity_R		0.044
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149736764; hg19: chr21-38137321;