Genetic Variant HLCS:c.*5010A>G (chr21-36749236-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001352514.2(HLCS):c.*5010A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 152,520 control chromosomes in the GnomAD database, including 22,621 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.54 ( 22573 hom., cov: 33)

Exomes 𝑓: 0.48 ( 48 hom. )

Consequence

HLCS
NM_001352514.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.189

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 links:

SIM2 (HGNC:10883): (SIM bHLH transcription factor 2) This gene represents a homolog of the Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of neurogenesis. The encoded protein is ubiquitinated by RING-IBR-RING-type E3 ubiquitin ligases, including the parkin RBR E3 ubiquitin protein ligase. This gene maps within the so-called Down syndrome chromosomal region, and is thus thought to contribute to some specific Down syndrome phenotypes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

SIM2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2 link	c.*5010A>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000674895.3	NP_001339443.1
SIM2	NM_005069.6 link	c.*1144T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000290399.11	NP_005060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895 link	c.*5010A>G		3_prime_UTR_variant	Exon 11 of 11		NM_001352514.2	ENSP00000502087.2		P50747-2A0A8C8QSB1
SIM2	ENST00000290399.11 link	c.*1144T>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_005069.6	ENSP00000290399.6		Q14190-1

Frequencies

GnomAD3 genomes

AF:

0.539

AC:

81898

AN:

151970

Hom.:

22563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.519

Gnomad AMI

AF:

0.696

Gnomad AMR

AF:

0.442

Gnomad ASJ

AF:

0.639

Gnomad EAS

AF:

0.286

Gnomad SAS

AF:

0.607

Gnomad FIN

AF:

0.522

Gnomad MID

AF:

0.693

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.551

GnomAD4 exome

AF:

0.479

AC:

208

AN:

434

Hom.:

Cov.:

AF XY:

0.469

AC XY:

122

AN XY:

260

show subpopulations

Gnomad4 AFR exome

AC:

AN:

Gnomad4 AMR exome

AC:

AN:

Gnomad4 ASJ exome

AC:

AN:

Gnomad4 EAS exome

AC:

AN:

Gnomad4 SAS exome

AC:

AN:

Gnomad4 FIN exome

AF:

0.479

AC:

204

AN:

426

Gnomad4 NFE exome

AF:

0.500

AC:

AN:

Gnomad4 Remaining exome

AF:

0.500

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome 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

GnomAD4 genome

AF:

0.539

AC:

81931

AN:

152086

Hom.:

22573

Cov.:

AF XY:

0.534

AC XY:

39698

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.519

AC:

0.519194

AN:

0.519194

Gnomad4 AMR

AF:

0.442

AC:

0.441581

AN:

0.441581

Gnomad4 ASJ

AF:

0.639

AC:

0.639193

AN:

0.639193

Gnomad4 EAS

AF:

0.285

AC:

0.285466

AN:

0.285466

Gnomad4 SAS

AF:

0.609

AC:

0.608669

AN:

0.608669

Gnomad4 FIN

AF:

0.522

AC:

0.521546

AN:

0.521546

Gnomad4 NFE

AF:

0.581

AC:

0.581394

AN:

0.581394

Gnomad4 OTH

AF:

0.545

AC:

0.545498

AN:

0.545498

Heterozygous variant carriers

1907

3813

5720

7626

9533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.560

Hom.:

45242

Bravo

AF:

0.528

Asia WGS

AF:

0.433

AC:

1500

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.72

DANN

Benign

0.30

Mutation Taster

=100/0

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over