21-36751624-C-T

Position:

• chr21-36751624-C-T

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.*2622G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 152,324 control chromosomes in the GnomAD database, including 14,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14295 hom., cov: 33)
  • Exomes 𝑓: 0.45 (15 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.449

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-36751624-C-T is Benign according to our data. Variant chr21-36751624-C-T is described in ClinVar as [Benign]. Clinvar id is 339920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.*2622G>A		3_prime_UTR_variant	11/11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895	c.*2622G>A		3_prime_UTR_variant	11/11		NM_001352514.2	ENSP00000502087.2
HLCS	ENST00000336648	c.*2622G>A		3_prime_UTR_variant	12/12	1		ENSP00000338387.3
HLCS	ENST00000399120	c.*2622G>A		3_prime_UTR_variant	12/12	1		ENSP00000382071.1
HLCS	ENST00000612277	c.*2622G>A		3_prime_UTR_variant	12/12	5		ENSP00000479939.1

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65430 AN: 152088 Hom.: 14275 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.459

GnomAD4 exome AF: 0.449 AC: 53 AN: 118 Hom.: 15 Cov.: 0 AF XY: 0.471 AC XY: 49 AN XY: 104

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.700

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.430 AC: 65468 AN: 152206 Hom.: 14295 Cov.: 33 AF XY: 0.430 AC XY: 32014 AN XY: 74388

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.490

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.596

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.459

Alfa AF: 0.449 Hom.: 6007

Bravo AF: 0.426

Asia WGS AF: 0.507 AC: 1760 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.52

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: rs14407; hg19: chr21-38123925;