21-36937159-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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

Publications

10 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, G2P, Labcorp Genetics (formerly Invitae), ClinGen

HLCS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001352514.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0016494691).

BP6

Variant 21-36937159-C-T is Benign according to our data. Variant chr21-36937159-C-T is described in ClinVar as Benign. ClinVar VariationId is 137550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 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	HGVSp	Effect	Exon Rank	Protein	UniProt
HLCS	NM_001352514.2	MANE Select	c.727G>A	p.Val243Ile	missense	Exon 4 of 11	NP_001339443.1	P50747-2
HLCS	NM_000411.8		c.286G>A	p.Val96Ile	missense	Exon 5 of 12	NP_000402.3
HLCS	NM_001242784.3		c.286G>A	p.Val96Ile	missense	Exon 5 of 12	NP_001229713.1	P50747-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLCS	ENST00000674895.3	MANE Select	c.727G>A	p.Val243Ile	missense	Exon 4 of 11	ENSP00000502087.2	P50747-2
HLCS	ENST00000336648.8	TSL:1	c.286G>A	p.Val96Ile	missense	Exon 5 of 12	ENSP00000338387.3	P50747-1
HLCS	ENST00000399120.5	TSL:1	c.286G>A	p.Val96Ile	missense	Exon 5 of 12	ENSP00000382071.1	P50747-1

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

GnomAD2 exomes

AF:

0.0217

AC:

5457

AN:

251442

AF XY:

0.0212

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 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

African (AFR)

AF:

0.110

AC:

3688

AN:

33480

American (AMR)

AF:

0.0100

AC:

447

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26134

East Asian (EAS)

AF:

0.0380

AC:

1509

AN:

39700

South Asian (SAS)

AF:

0.0466

AC:

4016

AN:

86258

European-Finnish (FIN)

AF:

0.0174

AC:

932

AN:

53410

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00483

AC:

5373

AN:

1112010

Other (OTH)

AF:

0.0161

AC:

974

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1262

2524

3787

5049

6311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.0398

AC:

6053

AN:

152228

Hom.:

258

Cov.:

AF XY:

0.0403

AC XY:

2997

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.112

AC:

4654

AN:

41512

American (AMR)

AF:

0.0199

AC:

304

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.0355

AC:

184

AN:

5178

South Asian (SAS)

AF:

0.0533

AC:

257

AN:

4826

European-Finnish (FIN)

AF:

0.0181

AC:

192

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00591

AC:

402

AN:

68024

Other (OTH)

AF:

0.0265

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

278

557

835

1114

1392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0154

Hom.:

299

Bravo

AF:

0.0410

Asia WGS

AF:

0.0470

AC:

163

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holocarboxylase synthetase deficiency (3)

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.0030

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.18

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.6

PhyloP100

-1.4

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.17

REVEL

Uncertain

0.30

Sift

Benign

0.23

Sift4G

Benign

0.54

Varity_R

0.024

gMVP

0.062

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over