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GeneBe

rs111603166

chr21-36930254-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001352514.2(HLCS):c.1617G>A(p.Ala539=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,614,064 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

HLCS
NM_001352514.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -8.22
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 21-36930254-C-T is Benign according to our data. Variant chr21-36930254-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 516115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-8.22 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00151 (230/152258) while in subpopulation AFR AF= 0.0053 (220/41548). AF 95% confidence interval is 0.00472. There are 2 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HLCSNM_001352514.2 linkuse as main transcriptc.1617G>A p.Ala539= synonymous_variant 5/11 ENST00000674895.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HLCSENST00000674895.3 linkuse as main transcriptc.1617G>A p.Ala539= synonymous_variant 5/11 NM_001352514.2 P4P50747-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00149
AC:
227
AN:
152140
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00524
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
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:
0.0000294
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000410
AC:
103
AN:
251416
Hom.:
1
AF XY:
0.000324
AC XY:
44
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.00547
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000152
AC:
222
AN:
1461806
Hom.:
0
Cov.:
33
AF XY:
0.000147
AC XY:
107
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00508
Gnomad4 AMR exome
AF:
0.000291
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00151
AC:
230
AN:
152258
Hom.:
2
Cov.:
32
AF XY:
0.00138
AC XY:
103
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.00530
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000916
Hom.:
0
Bravo
AF:
0.00171
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 24, 2024- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 16, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
Cadd
Benign
0.13
Dann
Benign
0.55
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs111603166; hg19: chr21-38302554; COSMIC: COSV100358173; API