21-36751019-C-CA

Position:

• chr21-36751019-C-CA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001352514.2(HLCS):​c.*3226dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 139,324 control chromosomes in the GnomAD database, including 502 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (502 hom., cov: 30)
  • Exomes 𝑓: 0.029 (0 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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]

HLCS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.*3226dupT		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.*3226dupT		3_prime_UTR_variant	11/11		NM_001352514.2	ENSP00000502087.2
HLCS	ENST00000336648	c.*3226dupT		3_prime_UTR_variant	12/12	1		ENSP00000338387.3
HLCS	ENST00000612277	c.*3226dupT		3_prime_UTR_variant	12/12	5		ENSP00000479939.1

Frequencies

GnomAD3 genomes AF: 0.0852 AC: 11858 AN: 139206 Hom.: 501 Cov.: 30

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.0702

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0778

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.0294 AC: 2 AN: 68 Hom.: 0 Cov.: 0 AF XY: 0.0588 AC XY: 2 AN XY: 34

Gnomad4 FIN exome AF: 0.0294

GnomAD4 genome AF: 0.0852 AC: 11870 AN: 139256 Hom.: 502 Cov.: 30 AF XY: 0.0852 AC XY: 5734 AN XY: 67274

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0700

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0570

Gnomad4 SAS AF: 0.0561

Gnomad4 FIN AF: 0.0695

Gnomad4 NFE AF: 0.0778

Gnomad4 OTH AF: 0.100

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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: rs35955622; hg19: chr21-38123320;