chr21-36937319-C-A

Position:

chr21-36937319-C-A

Variant summary

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

The NM_001352514.2(HLCS):c.567G>T(p.Glu189Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,022 control chromosomes in the GnomAD database, including 637 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E189E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.039 ( 245 hom., cov: 32)

Exomes 𝑓: 0.012 ( 392 hom. )

Consequence

HLCS
NM_001352514.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.453

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016950369).

BP6

Variant 21-36937319-C-A is Benign according to our data. Variant chr21-36937319-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 137548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36937319-C-A is described in Lovd as [Benign]. Variant chr21-36937319-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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.567G>T	p.Glu189Asp	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.567G>T	p.Glu189Asp	missense_variant	4/11		NM_001352514.2	ENSP00000502087	P4	P50747-2

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5903

AN:

152100

Hom.:

246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0359

Gnomad SAS

AF:

0.0531

Gnomad FIN

AF:

0.0181

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00591

Gnomad OTH

AF:

0.0272

GnomAD3 exomes

AF:

0.0216

AC:

5374

AN:

248804

Hom.:

172

AF XY:

0.0212

AC XY:

2850

AN XY:

134534

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.00926

Gnomad ASJ exome

AF:

0.00220

Gnomad EAS exome

AF:

0.0383

Gnomad SAS exome

AF:

0.0478

Gnomad FIN exome

AF:

0.0178

Gnomad NFE exome

AF:

0.00576

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0116

AC:

16928

AN:

1461804

Hom.:

392

Cov.:

AF XY:

0.0124

AC XY:

9051

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.107

Gnomad4 AMR exome

AF:

0.00966

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.0380

Gnomad4 SAS exome

AF:

0.0465

Gnomad4 FIN exome

AF:

0.0174

Gnomad4 NFE exome

AF:

0.00483

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0388

AC:

5908

AN:

152218

Hom.:

245

Cov.:

AF XY:

0.0394

AC XY:

2930

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.0196

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0361

Gnomad4 SAS

AF:

0.0529

Gnomad4 FIN

AF:

0.0181

Gnomad4 NFE

AF:

0.00591

Gnomad4 OTH

AF:

0.0265

Alfa

AF:

0.00677

Hom.:

Bravo

AF:

0.0401

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.104

AC:

458

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.0244

AC:

2958

Asia WGS

AF:

0.0470

AC:

163

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Holocarboxylase synthetase deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.30

CADD

Benign

0.98

DANN

Benign

0.88

DEOGEN2

Benign

0.25

T;T;T;.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.61

T;.;.;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.55

N;N;N;.;.;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.81

.;N;N;N;.;N

REVEL

Benign

0.19

Sift

Benign

0.36

.;T;T;T;.;T

Sift4G

Benign

0.37

T;T;T;.;.;T

Polyphen

0.16

B;B;B;.;.;.

Vest4

0.015

MutPred

0.14

Loss of glycosylation at P43 (P = 0.1345);Loss of glycosylation at P43 (P = 0.1345);Loss of glycosylation at P43 (P = 0.1345);Loss of glycosylation at P43 (P = 0.1345);.;Loss of glycosylation at P43 (P = 0.1345);

MPC

0.11

ClinPred

0.0040

GERP RS

2.5

Varity_R

0.053

gMVP

0.068

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

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