21-36759871-C-T

Variant names:

• chr21-36759871-C-T
• rs2073420
• NM_001352514.2:c.2122-30G>A

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 0.115
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• holocarboxylase synthetase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.2122-30G>A		intron_variant	Intron 8 of 10	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.2122-30G>A		intron_variant	Intron 8 of 10		NM_001352514.2	ENSP00000502087.2

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

GnomAD2 exomes AF: 0.431 AC: 108284 AN: 251052 AF XY: 0.444

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 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

African (AFR) AF: 0.315 AC: 9205 AN: 29226

American (AMR) AF: 0.331 AC: 14706 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 10944 AN: 24776

East Asian (EAS) AF: 0.302 AC: 11670 AN: 38686

South Asian (SAS) AF: 0.548 AC: 44941 AN: 81986

European-Finnish (FIN) AF: 0.385 AC: 20499 AN: 53272

Middle Eastern (MID) AF: 0.474 AC: 2537 AN: 5352

European-Non Finnish (NFE) AF: 0.476 AC: 433999 AN: 911956

Other (OTH) AF: 0.448 AC: 23796 AN: 53138

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

African (AFR) AF: 0.326 AC: 13487 AN: 41432

American (AMR) AF: 0.375 AC: 5737 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1558 AN: 3468

East Asian (EAS) AF: 0.307 AC: 1585 AN: 5156

South Asian (SAS) AF: 0.546 AC: 2625 AN: 4804

European-Finnish (FIN) AF: 0.393 AC: 4143 AN: 10554

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32144 AN: 67954

Other (OTH) AF: 0.430 AC: 902 AN: 2100

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Holocarboxylase synthetase deficiency Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2073420; hg19: chr21-38132172; COSMIC: COSV60792117;