chr21-36751019-CA-C

Position:

• chr21-36751019-CA-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.*3226delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 139,370 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: 30)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 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 = 0.00263 (366/139302) while in subpopulation NFE AF= 0.00327 (209/63842). AF 95% confidence interval is 0.00291. There are 1 homozygotes in gnomad4. There are 172 alleles in male gnomad4 subpopulation. Median coverage is 30. 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.*3226delT		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.*3226delT		3_prime_UTR_variant	11/11		NM_001352514.2	ENSP00000502087.2
HLCS	ENST00000336648	c.*3226delT		3_prime_UTR_variant	12/12	1		ENSP00000338387.3
HLCS	ENST00000612277	c.*3226delT		3_prime_UTR_variant	12/12	5		ENSP00000479939.1

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 363 AN: 139248 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00284

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00327

Gnomad OTH AF: 0.00264

GnomAD4 exome AF: 0.0147 AC: 1 AN: 68 Hom.: 0 Cov.: 0 AF XY: 0.0294 AC XY: 1 AN XY: 34

Gnomad4 FIN exome AF: 0.0147

GnomAD4 genome AF: 0.00263 AC: 366 AN: 139302 Hom.: 1 Cov.: 30 AF XY: 0.00256 AC XY: 172 AN XY: 67284

Gnomad4 AFR AF: 0.00268

Gnomad4 AMR AF: 0.00108

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00285

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00152

Gnomad4 NFE AF: 0.00327

Gnomad4 OTH AF: 0.00263

Alfa AF: 0.000138 Hom.: 8

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: rs35955622; hg19: chr21-38123320;