rs61732507

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001352514.2(HLCS):c.2361C>T(p.Val787Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00853 in 1,614,062 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V787V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 66 hom., cov: 31)

Exomes 𝑓: 0.0074 ( 85 hom. )

Consequence

HLCS
NM_001352514.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.67

Publications

3 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 21-36756631-G-A is Benign according to our data. Variant chr21-36756631-G-A is described in ClinVar as Benign. ClinVar VariationId is 137546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.67 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0193 (2931/152196) while in subpopulation AFR AF = 0.0508 (2110/41502). AF 95% confidence interval is 0.049. There are 66 homozygotes in GnomAd4. There are 1387 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2 link	c.2361C>T	p.Val787Val	synonymous_variant	Exon 10 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3 link	c.2361C>T	p.Val787Val	synonymous_variant	Exon 10 of 11		NM_001352514.2	ENSP00000502087.2		P50747-2A0A8C8QSB1

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2920

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0507

Gnomad AMI

AF:

0.0912

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00600

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.00938

AC:

2358

AN:

251494

AF XY:

0.00889

show subpopulations

Gnomad AFR exome

AF:

0.0504

Gnomad AMR exome

AF:

0.00688

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00596

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.00741

AC:

10834

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00742

AC XY:

5398

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0497

AC:

1663

AN:

33480

American (AMR)

AF:

0.00758

AC:

339

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

286

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.0138

AC:

1191

AN:

86250

European-Finnish (FIN)

AF:

0.00105

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00606

AC:

6740

AN:

1111994

Other (OTH)

AF:

0.00874

AC:

528

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

658

1316

1975

2633

3291

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:

0.0193

AC:

2931

AN:

152196

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1387

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0508

AC:

2110

AN:

41502

American (AMR)

AF:

0.0115

AC:

176

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.0118

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00600

AC:

408

AN:

68010

Other (OTH)

AF:

0.0208

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

139

279

418

558

697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0118

Hom.:

Bravo

AF:

0.0213

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00573

EpiControl

AF:

0.00504

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holocarboxylase synthetase deficiency

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Mar 19, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.0020

(source)

DANN

Benign

0.75

PhyloP100

-2.7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over