rs1555882090

Variant names:

• chr21-36756721-GGTA-G
• rs1555882090
• NM_001352514.2:c.2268_2270delTAC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001352514.2(HLCS):​c.2268_2270delTAC​(p.Thr757del) variant causes a disruptive inframe deletion 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P756P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HLCS NM_001352514.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.16
• 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001352514.2. Strenght limited to Supporting due to length of the change: 1aa.

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.2268_2270delTAC	p.Thr757del	disruptive_inframe_deletion	Exon 10 of 11	NP_001339443.1
	HLCS	NM_000411.8		c.1827_1829delTAC	p.Thr610del	disruptive_inframe_deletion	Exon 11 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.1827_1829delTAC	p.Thr610del	disruptive_inframe_deletion	Exon 11 of 12	NP_001229713.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.2268_2270delTAC	p.Thr757del	disruptive_inframe_deletion	Exon 10 of 11	ENSP00000502087.2
	HLCS	ENST00000336648.8	TSL:1	c.1827_1829delTAC	p.Thr610del	disruptive_inframe_deletion	Exon 11 of 12	ENSP00000338387.3
	HLCS	ENST00000399120.5	TSL:1	c.1827_1829delTAC	p.Thr610del	disruptive_inframe_deletion	Exon 11 of 12	ENSP00000382071.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Holocarboxylase synthetase deficiency (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=30/70	disease causing

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: rs1555882090; hg19: chr21-38129022;