dbSNP rs2073425: HLCS:c.1438-36G>A (chr21-36930469-C-T) – ACMG Classification: Benign (-20 pts)

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.1438-36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,522,762 control chromosomes in the GnomAD database, including 248,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23527 hom., cov: 31)

Exomes 𝑓: 0.57 ( 225417 hom. )

Consequence

HLCS
NM_001352514.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.265

Publications

12 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 (BayesDel_noAF=-0.82).

BP6

Variant 21-36930469-C-T is Benign according to our data. Variant chr21-36930469-C-T is described in ClinVar as Benign. ClinVar VariationId is 256037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.616 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	UniProt
HLCS	NM_001352514.2	MANE Select	c.1438-36G>A	intron	N/A	NP_001339443.1	P50747-2
HLCS	NM_000411.8		c.997-36G>A	intron	N/A	NP_000402.3
HLCS	NM_001242784.3		c.997-36G>A	intron	N/A	NP_001229713.1	P50747-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLCS	ENST00000674895.3	MANE Select	c.1438-36G>A	intron	N/A	ENSP00000502087.2	P50747-2
HLCS	ENST00000336648.8	TSL:1	c.997-36G>A	intron	N/A	ENSP00000338387.3	P50747-1
HLCS	ENST00000399120.5	TSL:1	c.997-36G>A	intron	N/A	ENSP00000382071.1	P50747-1

Frequencies

GnomAD3 genomes

AF:

0.553

AC:

83898

AN:

151712

Hom.:

23500

Cov.:

show subpopulations

Gnomad AFR

AF:

0.504

Gnomad AMI

AF:

0.476

Gnomad AMR

AF:

0.624

Gnomad ASJ

AF:

0.488

Gnomad EAS

AF:

0.634

Gnomad SAS

AF:

0.549

Gnomad FIN

AF:

0.586

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.561

Gnomad OTH

AF:

0.537

GnomAD2 exomes

AF:

0.591

AC:

147561

AN:

249662

AF XY:

0.586

show subpopulations

Gnomad AFR exome

AF:

0.503

Gnomad AMR exome

AF:

0.739

Gnomad ASJ exome

AF:

0.495

Gnomad EAS exome

AF:

0.649

Gnomad FIN exome

AF:

0.579

Gnomad NFE exome

AF:

0.567

Gnomad OTH exome

AF:

0.567

GnomAD4 exome

AF:

0.572

AC:

784847

AN:

1370932

Hom.:

225417

Cov.:

AF XY:

0.571

AC XY:

392561

AN XY:

687316

show subpopulations

African (AFR)

AF:

0.508

AC:

16003

AN:

31502

American (AMR)

AF:

0.728

AC:

32392

AN:

44470

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

12675

AN:

25564

East Asian (EAS)

AF:

0.637

AC:

25024

AN:

39310

South Asian (SAS)

AF:

0.573

AC:

47963

AN:

83746

European-Finnish (FIN)

AF:

0.584

AC:

31171

AN:

53358

Middle Eastern (MID)

AF:

0.480

AC:

2670

AN:

5560

European-Non Finnish (NFE)

AF:

0.568

AC:

584814

AN:

1030088

Other (OTH)

AF:

0.560

AC:

32135

AN:

57334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

15920

31840

47760

63680

79600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15942

31884

47826

63768

79710

<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:

0.553

AC:

83968

AN:

151830

Hom.:

23527

Cov.:

AF XY:

0.555

AC XY:

41161

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.504

AC:

20853

AN:

41366

American (AMR)

AF:

0.624

AC:

9539

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.488

AC:

1693

AN:

3470

East Asian (EAS)

AF:

0.634

AC:

3271

AN:

5160

South Asian (SAS)

AF:

0.548

AC:

2630

AN:

4796

European-Finnish (FIN)

AF:

0.586

AC:

6170

AN:

10530

Middle Eastern (MID)

AF:

0.459

AC:

135

AN:

294

European-Non Finnish (NFE)

AF:

0.561

AC:

38112

AN:

67922

Other (OTH)

AF:

0.539

AC:

1135

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1915

3829

5744

7658

9573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<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:

0.559

Hom.:

63867

Bravo

AF:

0.558

Asia WGS

AF:

0.542

AC:

1885

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Holocarboxylase synthetase deficiency (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.5

(source)

DANN

Benign

0.63

PhyloP100

-0.27

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

Computational scores

Splicing

Publications

Other links and lift over