Genetic Variant NM_001352514.2: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

Publications

8 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 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	ENST00000674895.3 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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.479

AC:

204

AN:

426

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.519

AC:

21532

AN:

41472

American (AMR)

AF:

0.442

AC:

6750

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.639

AC:

2218

AN:

3470

East Asian (EAS)

AF:

0.285

AC:

1477

AN:

5174

South Asian (SAS)

AF:

0.609

AC:

2935

AN:

4822

European-Finnish (FIN)

AF:

0.522

AC:

5519

AN:

10582

Middle Eastern (MID)

AF:

0.682

AC:

199

AN:

292

European-Non Finnish (NFE)

AF:

0.581

AC:

39515

AN:

67966

Other (OTH)

AF:

0.545

AC:

1151

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1907

3813

5720

7626

9533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

(source)

DANN

Benign

0.30

PhyloP100

-0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over