rs2073421

Variant names:

• chr21-36767331-C-A
• rs2073421
• NM_001352514.2:c.1893-46G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-36767331-C-A
• chr21-36767331-C-G
• chr21-36767331-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001352514.2(HLCS):​c.1893-46G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,580,300 control chromosomes in the GnomAD database, including 233,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26905 hom., cov: 31)
  • Exomes 𝑓: 0.53 (206182 hom.)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.208
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-36767331-C-A is Benign according to our data. Variant chr21-36767331-C-A is described in ClinVar as Benign. ClinVar VariationId is 256034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1893-46G>T		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.1893-46G>T		intron_variant	Intron 6 of 10		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.589 AC: 89404 AN: 151846 Hom.: 26847 Cov.: 31

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.572

GnomAD2 exomes AF: 0.568 AC: 142613 AN: 251048 AF XY: 0.555

Gnomad AFR exome AF: 0.700

Gnomad AMR exome AF: 0.674

Gnomad ASJ exome AF: 0.560

Gnomad EAS exome AF: 0.657

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.562

GnomAD4 exome AF: 0.534 AC: 763109 AN: 1428336 Hom.: 206182 Cov.: 25 AF XY: 0.531 AC XY: 378170 AN XY: 712602

African (AFR) AF: 0.708 AC: 23260 AN: 32866

American (AMR) AF: 0.669 AC: 29864 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14430 AN: 25918

East Asian (EAS) AF: 0.697 AC: 27583 AN: 39558

South Asian (SAS) AF: 0.467 AC: 39959 AN: 85500

European-Finnish (FIN) AF: 0.614 AC: 32788 AN: 53386

Middle Eastern (MID) AF: 0.528 AC: 3004 AN: 5690

European-Non Finnish (NFE) AF: 0.517 AC: 559659 AN: 1081470

Other (OTH) AF: 0.549 AC: 32562 AN: 59282

GnomAD4 genome AF: 0.589 AC: 89519 AN: 151964 Hom.: 26905 Cov.: 31 AF XY: 0.592 AC XY: 43955 AN XY: 74300

African (AFR) AF: 0.696 AC: 28837 AN: 41454

American (AMR) AF: 0.619 AC: 9447 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1908 AN: 3468

East Asian (EAS) AF: 0.687 AC: 3547 AN: 5160

South Asian (SAS) AF: 0.472 AC: 2272 AN: 4810

European-Finnish (FIN) AF: 0.606 AC: 6411 AN: 10574

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.520 AC: 35322 AN: 67938

Other (OTH) AF: 0.575 AC: 1212 AN: 2106

Alfa AF: 0.565 Hom.: 4845

Bravo AF: 0.596

Asia WGS AF: 0.587 AC: 2041 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Holocarboxylase synthetase deficiency Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.49
DANN	Benign	0.53
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: rs2073421; hg19: chr21-38139632;