rs61732502

Positions:

chr21-36937159-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.37

Variant links:

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]

HLCS links:

HLCS (HGNC:):

HLCS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
HLCS	NM_001352514.2 linkuse as main transcript	c.727G>A	p.Val243Ile	missense_variant	4/11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3 linkuse as main transcript	c.727G>A	p.Val243Ile	missense_variant	4/11		NM_001352514.2	ENSP00000502087.2		P50747-2A0A8C8QSB1

Frequencies

GnomAD3 genomes

AF:

0.0397

AC:

6046

AN:

152110

Hom.:

259

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0125

AC XY:

9104

AN XY:

727244

show subpopulations

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.:

AF XY:

0.0403

AC XY:

2997

AN XY:

74426

show subpopulations

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.:

Bravo

AF:

0.0410

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.107

AC:

471

ESP6500EA

AF:

0.00512

AC:

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Holocarboxylase synthetase deficiency

Benign:3

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

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.51

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

LIST_S2

Benign

0.15

T;.;.

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.17

.;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.23

.;T;T

Sift4G

Benign

0.54

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.014

MPC

0.099

ClinPred

0.0078

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over