21-36751019-CAA-CAAA

Variant names:

• chr21-36751019-C-CA
• rs35955622
• NM_001352514.2:c.*3226dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001352514.2(HLCS):​c.*3226dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 139,324 control chromosomes in the GnomAD database, including 502 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (502 hom., cov: 30)
  • Exomes 𝑓: 0.029 (0 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.208
• 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, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

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.*3226dupT		3_prime_UTR	Exon 11 of 11	NP_001339443.1	P50747-2
	HLCS	NM_000411.8		c.*3226dupT		3_prime_UTR	Exon 12 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.*3226dupT		3_prime_UTR	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.*3226dupT		3_prime_UTR	Exon 11 of 11	ENSP00000502087.2	P50747-2
	HLCS	ENST00000336648.8	TSL:1	c.*3226dupT		3_prime_UTR	Exon 12 of 12	ENSP00000338387.3	P50747-1
	HLCS	ENST00000612277.4	TSL:5	c.*3226dupT		3_prime_UTR	Exon 12 of 12	ENSP00000479939.1	P50747-1

Frequencies

GnomAD3 genomes AF: 0.0852 AC: 11858 AN: 139206 Hom.: 501 Cov.: 30

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.0702

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0569

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0778

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.0294 AC: 2 AN: 68 Hom.: 0 Cov.: 0 AF XY: 0.0588 AC XY: 2 AN XY: 34

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0294 AC: 2 AN: 68

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0852 AC: 11870 AN: 139256 Hom.: 502 Cov.: 30 AF XY: 0.0852 AC XY: 5734 AN XY: 67274

African (AFR) AF: 0.106 AC: 4020 AN: 38048

American (AMR) AF: 0.0700 AC: 975 AN: 13922

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 436 AN: 3314

East Asian (EAS) AF: 0.0570 AC: 280 AN: 4912

South Asian (SAS) AF: 0.0561 AC: 239 AN: 4262

European-Finnish (FIN) AF: 0.0695 AC: 550 AN: 7916

Middle Eastern (MID) AF: 0.197 AC: 54 AN: 274

European-Non Finnish (NFE) AF: 0.0778 AC: 4965 AN: 63830

Other (OTH) AF: 0.100 AC: 191 AN: 1904

Alfa AF: 0.0173 Hom.: 8

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs35955622; hg19: chr21-38123320; COSMIC: COSV51767750; COSMIC: COSV51767750;