chr21-36936474-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001352514.2(HLCS):c.1412G>A(p.Arg471His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,160 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R471R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0087 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 109 hom. )

Consequence

HLCS
NM_001352514.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.11

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

holocarboxylase synthetase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

HLCS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006816119).

BP6

Variant 21-36936474-C-T is Benign according to our data. Variant chr21-36936474-C-T is described in ClinVar as Benign. ClinVar VariationId is 137551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00872 (1328/152352) while in subpopulation SAS AF = 0.0164 (79/4824). AF 95% confidence interval is 0.0135. There are 7 homozygotes in GnomAd4. There are 678 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2 link	c.1412G>A	p.Arg471His	missense_variant	Exon 4 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3 link	c.1412G>A	p.Arg471His	missense_variant	Exon 4 of 11		NM_001352514.2	ENSP00000502087.2		P50747-2A0A8C8QSB1

Frequencies

GnomAD3 genomes

AF:

0.00872

AC:

1327

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.0172

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.0100

AC:

2503

AN:

249592

AF XY:

0.0111

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0112

AC:

16420

AN:

1461808

Hom.:

109

Cov.:

AF XY:

0.0115

AC XY:

8330

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33478

American (AMR)

AF:

0.00483

AC:

216

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

264

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0164

AC:

1418

AN:

86256

European-Finnish (FIN)

AF:

0.0161

AC:

858

AN:

53416

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0116

AC:

12854

AN:

1111936

Other (OTH)

AF:

0.0112

AC:

679

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

910

1820

2730

3640

4550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

496

992

1488

1984

2480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00872

AC:

1328

AN:

152352

Hom.:

Cov.:

AF XY:

0.00910

AC XY:

678

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00262

AC:

109

AN:

41580

American (AMR)

AF:

0.00712

AC:

109

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00950

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0164

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0172

AC:

183

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

795

AN:

68034

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00865

Hom.:

Bravo

AF:

0.00741

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.00974

AC:

1182

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0123

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holocarboxylase synthetase deficiency

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:1

Oct 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.021

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.057

T;.;.

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

-0.51

N;N;N

PhyloP100

-2.1

PrimateAI

Benign

0.20

PROVEAN

Benign

0.46

.;N;N

REVEL

Benign

0.21

Sift

Benign

0.30

.;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.047

MPC

0.15

ClinPred

0.0051

GERP RS

-8.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.32

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over