rs2073420

chr21-36759871-C-Tchr21-36759871-C-Gchr21-36759871-C-A

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.2122-30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,394,790 control chromosomes in the GnomAD database, including 147,121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13405 hom., cov: 32)
  • Exomes 𝑓: 0.46 (133716 hom.)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.115

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=-0.83).
• BP6: Variant 21-36759871-C-T is Benign according to our data. Variant chr21-36759871-C-T is described in ClinVar as [Benign]. Clinvar id is 256035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.2122-30G>A		intron_variant		ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.2122-30G>A		intron_variant			NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62817 AN: 151836 Hom.: 13404 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.433

GnomAD3 exomes AF: 0.431 AC: 108284 AN: 251052 Hom.: 24149 AF XY: 0.444 AC XY: 60350 AN XY: 135794

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.548

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.438

GnomAD4 exome AF: 0.460 AC: 572297 AN: 1242836 Hom.: 133716 Cov.: 18 AF XY: 0.466 AC XY: 293232 AN XY: 629918

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.442

Gnomad4 EAS exome AF: 0.302

Gnomad4 SAS exome AF: 0.548

Gnomad4 FIN exome AF: 0.385

Gnomad4 NFE exome AF: 0.476

Gnomad4 OTH exome AF: 0.448

GnomAD4 genome AF: 0.413 AC: 62821 AN: 151954 Hom.: 13405 Cov.: 32 AF XY: 0.412 AC XY: 30567 AN XY: 74272

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.546

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.430

Alfa AF: 0.374 Hom.: 2047

Bravo AF: 0.407

Asia WGS AF: 0.411 AC: 1429 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

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.1
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2073420; hg19: chr21-38132172; COSMIC: COSV60792117;