chr21-36751019-C-CAA

Variant names:

• chr21-36751019-C-CAA
• rs35955622
• NM_001352514.2:c.*3225_*3226dupTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001352514.2(HLCS):​c.*3225_*3226dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 139,452 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (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

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.*3225_*3226dupTT		3_prime_UTR_variant	Exon 11 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895	c.*3225_*3226dupTT		3_prime_UTR_variant	Exon 11 of 11		NM_001352514.2	ENSP00000502087.2
HLCS	ENST00000336648	c.*3225_*3226dupTT		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000338387.3
HLCS	ENST00000612277	c.*3225_*3226dupTT		3_prime_UTR_variant	Exon 12 of 12	5		ENSP00000479939.1
HLCS	ENST00000399120.5	c.*3225_*3226dupTT		downstream_gene_variant		1		ENSP00000382071.1

Frequencies

GnomAD3 genomes AF: 0.000115 AC: 16 AN: 139398 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000718

Gnomad ASJ AF: 0.00121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000782

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

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.000122 AC: 17 AN: 139452 Hom.: 0 Cov.: 30 AF XY: 0.000134 AC XY: 9 AN XY: 67380

Gnomad4 AFR AF: 0.000158

Gnomad4 AMR AF: 0.0000717

Gnomad4 ASJ AF: 0.00121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000126

Gnomad4 NFE AF: 0.0000782

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35955622; hg19: chr21-38123320;