rs61732504

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.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. 16/21 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

Publications

13 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: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

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=0.0016950369).

BP6

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

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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.567G>T	p.Glu189Asp	missense	Exon 4 of 11	NP_001339443.1	P50747-2
HLCS	NM_000411.8		c.126G>T	p.Glu42Asp	missense	Exon 5 of 12	NP_000402.3
HLCS	NM_001242784.3		c.126G>T	p.Glu42Asp	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.567G>T	p.Glu189Asp	missense	Exon 4 of 11	ENSP00000502087.2	P50747-2
HLCS	ENST00000336648.8	TSL:1	c.126G>T	p.Glu42Asp	missense	Exon 5 of 12	ENSP00000338387.3	P50747-1
HLCS	ENST00000399120.5	TSL:1	c.126G>T	p.Glu42Asp	missense	Exon 5 of 12	ENSP00000382071.1	P50747-1

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

GnomAD2 exomes

AF:

0.0216

AC:

5374

AN:

248804

AF XY:

0.0212

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 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

African (AFR)

AF:

0.107

AC:

3591

AN:

33478

American (AMR)

AF:

0.00966

AC:

432

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26132

East Asian (EAS)

AF:

0.0380

AC:

1509

AN:

39700

South Asian (SAS)

AF:

0.0465

AC:

4015

AN:

86254

European-Finnish (FIN)

AF:

0.0174

AC:

930

AN:

53362

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00483

AC:

5366

AN:

1111992

Other (OTH)

AF:

0.0160

AC:

966

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1019

2037

3056

4074

5093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.0388

AC:

5908

AN:

152218

Hom.:

245

Cov.:

AF XY:

0.0394

AC XY:

2930

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.109

AC:

4513

AN:

41498

American (AMR)

AF:

0.0196

AC:

299

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.0361

AC:

187

AN:

5174

South Asian (SAS)

AF:

0.0529

AC:

255

AN:

4820

European-Finnish (FIN)

AF:

0.0181

AC:

192

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00591

AC:

402

AN:

68028

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

271

541

812

1082

1353

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:

0.0169

Hom.:

198

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Holocarboxylase synthetase deficiency (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.30

CADD

Benign

0.98

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.25

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.55

PhyloP100

-0.45

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.81

REVEL

Benign

0.19

Sift

Benign

0.36

Sift4G

Benign

0.37

Polyphen

0.16

Vest4

0.015

MutPred

0.14

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

Mutation Taster

=96/4

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

Computational scores

Splicing

Publications

Other links and lift over