Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001352514.2(HLCS):c.2432A>G(p.Tyr811Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,603,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Y811Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

HLCS
NM_001352514.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.33

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

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
HLCS	NM_001352514.2	MANE Select	c.2432A>G	p.Tyr811Cys	missense	Exon 10 of 11	NP_001339443.1
HLCS	NM_000411.8		c.1991A>G	p.Tyr664Cys	missense	Exon 11 of 12	NP_000402.3
HLCS	NM_001242784.3		c.1991A>G	p.Tyr664Cys	missense	Exon 11 of 12	NP_001229713.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLCS	ENST00000674895.3	MANE Select	c.2432A>G	p.Tyr811Cys	missense	Exon 10 of 11	ENSP00000502087.2
HLCS	ENST00000336648.8	TSL:1	c.1991A>G	p.Tyr664Cys	missense	Exon 11 of 12	ENSP00000338387.3
HLCS	ENST00000399120.5	TSL:1	c.1991A>G	p.Tyr664Cys	missense	Exon 11 of 12	ENSP00000382071.1

Frequencies

GnomAD3 genomes

AF:

0.0000933

AC:

AN:

150036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000493

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000197

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000127

AC:

AN:

251492

AF XY:

0.000155

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000970

AC:

141

AN:

1453402

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

722932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33214

American (AMR)

AF:

0.000135

AC:

AN:

44424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25878

East Asian (EAS)

AF:

0.00

AC:

AN:

39038

South Asian (SAS)

AF:

0.00

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.000511

AC:

AN:

52796

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000913

AC:

101

AN:

1106366

Other (OTH)

AF:

0.000100

AC:

AN:

59800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000933

AC:

AN:

150036

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73170

show subpopulations

African (AFR)

AF:

0.0000493

AC:

AN:

40604

American (AMR)

AF:

0.00

AC:

AN:

15064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5102

South Asian (SAS)

AF:

0.00

AC:

AN:

4722

European-Finnish (FIN)

AF:

0.000197

AC:

AN:

10174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000148

AC:

AN:

67616

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000154

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holocarboxylase synthetase deficiency (3)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

PhyloP100

7.3

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.96

MVP

0.99

MPC

0.65

ClinPred

0.95

GERP RS

4.7

Varity_R

0.89

gMVP

0.83

Mutation Taster

=38/62

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr21-36756560-T-C

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over