chr21-36930243-CA-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001352514.2(HLCS):c.1620+7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,368 control chromosomes in the GnomAD database, including 25,229 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1587 hom., cov: 30)

Exomes 𝑓: 0.17 ( 23642 hom. )

Consequence

HLCS
NM_001352514.2 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.51

Publications

1 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 -16 ACMG points.

BP6

Variant 21-36930243-CA-C is Benign according to our data. Variant chr21-36930243-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352514.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HLCS	NM_001352514.2	MANE Select	c.1620+7delT	splice_region intron	N/A	NP_001339443.1
HLCS	NM_000411.8		c.1179+7delT	splice_region intron	N/A	NP_000402.3
HLCS	NM_001242784.3		c.1179+7delT	splice_region intron	N/A	NP_001229713.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HLCS	ENST00000674895.3	MANE Select	c.1620+7delT	splice_region intron	N/A	ENSP00000502087.2
HLCS	ENST00000336648.8	TSL:1	c.1179+7delT	splice_region intron	N/A	ENSP00000338387.3
HLCS	ENST00000399120.5	TSL:1	c.1179+7delT	splice_region intron	N/A	ENSP00000382071.1

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19232

AN:

152114

Hom.:

1588

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0354

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0994

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.0866

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.134

AC:

33730

AN:

251328

AF XY:

0.138

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.0755

Gnomad ASJ exome

AF:

0.183

Gnomad EAS exome

AF:

0.00359

Gnomad FIN exome

AF:

0.186

Gnomad NFE exome

AF:

0.186

Gnomad OTH exome

AF:

0.146

GnomAD4 exome

AF:

0.173

AC:

252293

AN:

1461136

Hom.:

23642

Cov.:

AF XY:

0.171

AC XY:

124155

AN XY:

726882

show subpopulations

African (AFR)

AF:

0.0285

AC:

953

AN:

33470

American (AMR)

AF:

0.0789

AC:

3530

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

4766

AN:

26134

East Asian (EAS)

AF:

0.00154

AC:

AN:

39698

South Asian (SAS)

AF:

0.0901

AC:

7775

AN:

86248

European-Finnish (FIN)

AF:

0.179

AC:

9576

AN:

53408

Middle Eastern (MID)

AF:

0.140

AC:

806

AN:

5766

European-Non Finnish (NFE)

AF:

0.194

AC:

215260

AN:

1111324

Other (OTH)

AF:

0.158

AC:

9566

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

9576

19153

28729

38306

47882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7338

14676

22014

29352

36690

<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:

0.126

AC:

19227

AN:

152232

Hom.:

1587

Cov.:

AF XY:

0.123

AC XY:

9184

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0353

AC:

1467

AN:

41558

American (AMR)

AF:

0.0992

AC:

1517

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

659

AN:

3470

East Asian (EAS)

AF:

0.00212

AC:

AN:

5182

South Asian (SAS)

AF:

0.0867

AC:

418

AN:

4822

European-Finnish (FIN)

AF:

0.182

AC:

1930

AN:

10600

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.190

AC:

12885

AN:

67986

Other (OTH)

AF:

0.130

AC:

275

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

859

1718

2577

3436

4295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.164

Hom.:

394

Bravo

AF:

0.118

Asia WGS

AF:

0.0610

AC:

212

AN:

3478

EpiCase

AF:

0.187

EpiControl

AF:

0.189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 16, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Holocarboxylase synthetase deficiency

Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Jun 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over