21-36751083-CACTT-C

Position:

• chr21-36751083-CACTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_001352514.2(HLCS):​c.*3159_*3162delAAGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 140,418 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (362/140028) while in subpopulation NFE AF= 0.00358 (227/63418). AF 95% confidence interval is 0.0032. There are 1 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.*3159_*3162delAAGT		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.*3159_*3162delAAGT		3_prime_UTR_variant	11/11		NM_001352514.2	ENSP00000502087.2
HLCS	ENST00000336648	c.*3159_*3162delAAGT		3_prime_UTR_variant	12/12	1		ENSP00000338387.3
HLCS	ENST00000612277	c.*3159_*3162delAAGT		3_prime_UTR_variant	12/12	5		ENSP00000479939.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 362 AN: 139984 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000835

Gnomad AMI AF: 0.00239

Gnomad AMR AF: 0.00202

Gnomad ASJ AF: 0.000315

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000698

Gnomad FIN AF: 0.00741

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00358

Gnomad OTH AF: 0.00159

GnomAD4 exome AF: 0.00256 AC: 1 AN: 390 Hom.: 0 AF XY: 0.00420 AC XY: 1 AN XY: 238

Gnomad4 FIN exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00259 AC: 362 AN: 140028 Hom.: 1 Cov.: 32 AF XY: 0.00256 AC XY: 174 AN XY: 67862

Gnomad4 AFR AF: 0.000834

Gnomad4 AMR AF: 0.00202

Gnomad4 ASJ AF: 0.000315

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000701

Gnomad4 FIN AF: 0.00741

Gnomad4 NFE AF: 0.00358

Gnomad4 OTH AF: 0.00158

Alfa AF: 0.00286 Hom.: 0

Bravo AF: 0.00215

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holocarboxylase synthetase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs535525635; hg19: chr21-38123384;