rs2073421

Positions:

• chr21-36767331-C-A
• chr21-36767331-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001352514.2(HLCS):​c.1893-46G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,580,300 control chromosomes in the GnomAD database, including 233,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26905 hom., cov: 31)
  • Exomes 𝑓: 0.53 (206182 hom.)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.208

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-36767331-C-A is Benign according to our data. Variant chr21-36767331-C-A is described in ClinVar as [Benign]. Clinvar id is 256034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.1893-46G>T		intron_variant		ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.1893-46G>T		intron_variant			NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.589 AC: 89404 AN: 151846 Hom.: 26847 Cov.: 31

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.572

GnomAD3 exomes AF: 0.568 AC: 142613 AN: 251048 Hom.: 41302 AF XY: 0.555 AC XY: 75365 AN XY: 135704

Gnomad AFR exome AF: 0.700

Gnomad AMR exome AF: 0.674

Gnomad ASJ exome AF: 0.560

Gnomad EAS exome AF: 0.657

Gnomad SAS exome AF: 0.467

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.562

GnomAD4 exome AF: 0.534 AC: 763109 AN: 1428336 Hom.: 206182 Cov.: 25 AF XY: 0.531 AC XY: 378170 AN XY: 712602

Gnomad4 AFR exome AF: 0.708

Gnomad4 AMR exome AF: 0.669

Gnomad4 ASJ exome AF: 0.557

Gnomad4 EAS exome AF: 0.697

Gnomad4 SAS exome AF: 0.467

Gnomad4 FIN exome AF: 0.614

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.549

GnomAD4 genome AF: 0.589 AC: 89519 AN: 151964 Hom.: 26905 Cov.: 31 AF XY: 0.592 AC XY: 43955 AN XY: 74300

Gnomad4 AFR AF: 0.696

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.687

Gnomad4 SAS AF: 0.472

Gnomad4 FIN AF: 0.606

Gnomad4 NFE AF: 0.520

Gnomad4 OTH AF: 0.575

Alfa AF: 0.565 Hom.: 4845

Bravo AF: 0.596

Asia WGS AF: 0.587 AC: 2041 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Holocarboxylase synthetase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.49
DANN	Benign	0.53

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

Other links and lift over

dbSNP: rs2073421; hg19: chr21-38139632;