rs765321

Variant names:

• chr21-36815845-G-T
• rs765321
• NM_001352514.2:c.1893-48560C>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.1893-48560C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,014 control chromosomes in the GnomAD database, including 7,974 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 0.31 (7974 hom., cov: 32)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.552
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1893-48560C>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.1893-48560C>A		intron_variant	Intron 6 of 10		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47630 AN: 151896 Hom.: 7964 Cov.: 32

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.0786

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.325

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

GnomAD4 genome AF: 0.314 AC: 47682 AN: 152014 Hom.: 7974 Cov.: 32 AF XY: 0.307 AC XY: 22823 AN XY: 74302

African (AFR) AF: 0.403 AC: 16694 AN: 41422

American (AMR) AF: 0.230 AC: 3508 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 825 AN: 3472

East Asian (EAS) AF: 0.0780 AC: 404 AN: 5182

South Asian (SAS) AF: 0.242 AC: 1165 AN: 4814

European-Finnish (FIN) AF: 0.260 AC: 2743 AN: 10570

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21274 AN: 67958

Other (OTH) AF: 0.324 AC: 685 AN: 2116

Alfa AF: 0.308 Hom.: 4445

Bravo AF: 0.313

Asia WGS AF: 0.184 AC: 642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.18
DANN	Benign	0.45
PhyloP100		-0.55
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: rs765321; hg19: chr21-38188145;