21-36863977-C-T

Variant names:

• chr21-36863977-C-T
• rs7282868
• NM_001352514.2:c.1892+32883G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001352514.2(HLCS):​c.1892+32883G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 152,196 control chromosomes in the GnomAD database, including 3,198 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3198 hom., cov: 33)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1892+32883G>A		intron_variant	Intron 6 of 10	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.1892+32883G>A		intron_variant	Intron 6 of 10		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30054 AN: 152078 Hom.: 3194 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.0819

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.198 AC: 30079 AN: 152196 Hom.: 3198 Cov.: 33 AF XY: 0.193 AC XY: 14392 AN XY: 74422

African (AFR) AF: 0.244 AC: 10125 AN: 41502

American (AMR) AF: 0.216 AC: 3304 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 710 AN: 3472

East Asian (EAS) AF: 0.148 AC: 765 AN: 5170

South Asian (SAS) AF: 0.175 AC: 846 AN: 4822

European-Finnish (FIN) AF: 0.0819 AC: 869 AN: 10610

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12493 AN: 68006

Other (OTH) AF: 0.222 AC: 468 AN: 2110

Alfa AF: 0.112 Hom.: 219

Bravo AF: 0.206

Asia WGS AF: 0.167 AC: 584 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.8
DANN	Benign	0.74
PhyloP100		0.037
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: rs7282868; hg19: chr21-38236277;