21-36751019-CAA-CAAAAAA

Variant names:

• chr21-36751019-C-CAAAA
• rs35955622
• NM_001352514.2:c.*3223_*3226dupTTTT

Variant summary

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

The NM_001352514.2(HLCS):​c.*3223_*3226dupTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.*3223_*3226dupTTTT		3_prime_UTR	Exon 11 of 11	NP_001339443.1	P50747-2
	HLCS	NM_000411.8		c.*3223_*3226dupTTTT		3_prime_UTR	Exon 12 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.*3223_*3226dupTTTT		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.*3223_*3226dupTTTT		3_prime_UTR	Exon 11 of 11	ENSP00000502087.2	P50747-2
	HLCS	ENST00000336648.8	TSL:1	c.*3223_*3226dupTTTT		3_prime_UTR	Exon 12 of 12	ENSP00000338387.3	P50747-1
	HLCS	ENST00000612277.4	TSL:5	c.*3223_*3226dupTTTT		3_prime_UTR	Exon 12 of 12	ENSP00000479939.1	P50747-1

Frequencies

GnomAD3 genomes AF: 0.0000359 AC: 5 AN: 139398 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000156

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 68 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000359 AC: 5 AN: 139398 Hom.: 0 Cov.: 30 AF XY: 0.0000743 AC XY: 5 AN XY: 67304

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000263 AC: 1 AN: 37994

American (AMR) AF: 0.00 AC: 0 AN: 13926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.00 AC: 0 AN: 4926

South Asian (SAS) AF: 0.00 AC: 0 AN: 4288

European-Finnish (FIN) AF: 0.000378 AC: 3 AN: 7946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000156 AC: 1 AN: 63936

Other (OTH) AF: 0.00 AC: 0 AN: 1896

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000207 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35955622; hg19: chr21-38123320;