rs765321

Positions:

• chr21-36815845-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001352514.2(HLCS):​c.1893-48560C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,014 control chromosomes in the GnomAD database, including 7,974 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7974 hom., cov: 32)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.552

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1893-48560C>A		intron_variant		ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.1893-48560C>A		intron_variant			NM_001352514.2	ENSP00000502087	P4

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47630 AN: 151896 Hom.: 7964 Cov.: 32

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.0786

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.325

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.314 AC: 47682 AN: 152014 Hom.: 7974 Cov.: 32 AF XY: 0.307 AC XY: 22823 AN XY: 74302

Gnomad4 AFR AF: 0.403

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.0780

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.324

Alfa AF: 0.307 Hom.: 3998

Bravo AF: 0.313

Asia WGS AF: 0.184 AC: 642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.18
DANN	Benign	0.45

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: rs765321; hg19: chr21-38188145;