dbSNP rs75867009: HLCS:p.Gly657Arg (chr21-36765164-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001352514.2(HLCS):c.1969G>A(p.Gly657Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,204 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G657A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0059 ( 14 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 10 hom. )

Consequence

HLCS
NM_001352514.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.227

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: 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 -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001352514.2

BP4

Computational evidence support a benign effect (MetaRNN=0.014004856).

BP6

Variant 21-36765164-C-T is Benign according to our data. Variant chr21-36765164-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00592 (902/152320) while in subpopulation AFR AF = 0.0203 (845/41578). AF 95% confidence interval is 0.0192. There are 14 homozygotes in GnomAd4. There are 421 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

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.1969G>A	p.Gly657Arg	missense	Exon 8 of 11	NP_001339443.1	P50747-2
HLCS	NM_000411.8		c.1528G>A	p.Gly510Arg	missense	Exon 9 of 12	NP_000402.3
HLCS	NM_001242784.3		c.1528G>A	p.Gly510Arg	missense	Exon 9 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.1969G>A	p.Gly657Arg	missense	Exon 8 of 11	ENSP00000502087.2	P50747-2
HLCS	ENST00000336648.8	TSL:1	c.1528G>A	p.Gly510Arg	missense	Exon 9 of 12	ENSP00000338387.3	P50747-1
HLCS	ENST00000399120.5	TSL:1	c.1528G>A	p.Gly510Arg	missense	Exon 9 of 12	ENSP00000382071.1	P50747-1

Frequencies

GnomAD3 genomes

AF:

0.00591

AC:

900

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00143

AC:

360

AN:

251396

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000625

AC:

913

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000549

AC XY:

399

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0228

AC:

763

AN:

33480

American (AMR)

AF:

0.000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1112006

Other (OTH)

AF:

0.00142

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

104

157

209

261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00592

AC:

902

AN:

152320

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

421

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0203

AC:

845

AN:

41578

American (AMR)

AF:

0.00288

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00241

Hom.:

Bravo

AF:

0.00691

ESP6500AA

AF:

0.0172

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00174

AC:

211

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holocarboxylase synthetase deficiency (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.25

CADD

Benign

3.8

(source)

DANN

Benign

0.82

DEOGEN2

Pathogenic

0.80

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.62

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.9

PhyloP100

0.23

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.34

Sift

Benign

0.40

Sift4G

Benign

0.70

Polyphen

0.0050

Vest4

0.31

MutPred

0.86

Gain of methylation at G510 (P = 0.0197)

MVP

0.84

MPC

0.15

ClinPred

0.024

GERP RS

-4.1

Varity_R

0.11

gMVP

0.51

Mutation Taster

=99/1

polymorphism

(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.

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