rs1555880930

Variant names:

• chr21-36754300-CG-C
• rs1555880930
• NM_001352514.2:c.2567delC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001352514.2(HLCS):​c.2567delC​(p.Pro856ArgfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. P856P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HLCS NM_001352514.2 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.99
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• holocarboxylase synthetase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.021 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352514.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	NM_001352514.2	MANE Select	c.2567delC	p.Pro856ArgfsTer9	frameshift	Exon 11 of 11	NP_001339443.1	P50747-2
	HLCS	NM_000411.8		c.2126delC	p.Pro709ArgfsTer9	frameshift	Exon 12 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.2126delC	p.Pro709ArgfsTer9	frameshift	Exon 12 of 12	NP_001229713.1	P50747-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.2567delC	p.Pro856ArgfsTer9	frameshift	Exon 11 of 11	ENSP00000502087.2	P50747-2
	HLCS	ENST00000336648.8	TSL:1	c.2126delC	p.Pro709ArgfsTer9	frameshift	Exon 12 of 12	ENSP00000338387.3	P50747-1
	HLCS	ENST00000399120.5	TSL:1	c.2126delC	p.Pro709ArgfsTer9	frameshift	Exon 12 of 12	ENSP00000382071.1	P50747-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Holocarboxylase synthetase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0

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

Other links and lift over

dbSNP: rs1555880930; hg19: chr21-38126601;