rs2073425

Variant names:

• chr21-36930469-C-T
• rs2073425
• NM_001352514.2:c.1438-36G>A

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.1438-36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,522,762 control chromosomes in the GnomAD database, including 248,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23527 hom., cov: 31)
  • Exomes 𝑓: 0.57 (225417 hom.)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.265
• Publications: 12 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=-0.82).
• BP6: Variant 21-36930469-C-T is Benign according to our data. Variant chr21-36930469-C-T is described in ClinVar as Benign. ClinVar VariationId is 256037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1438-36G>A		intron_variant	Intron 4 of 10	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.1438-36G>A		intron_variant	Intron 4 of 10		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.553 AC: 83898 AN: 151712 Hom.: 23500 Cov.: 31

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.537

GnomAD2 exomes AF: 0.591 AC: 147561 AN: 249662 AF XY: 0.586

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.649

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.567

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.572 AC: 784847 AN: 1370932 Hom.: 225417 Cov.: 21 AF XY: 0.571 AC XY: 392561 AN XY: 687316

African (AFR) AF: 0.508 AC: 16003 AN: 31502

American (AMR) AF: 0.728 AC: 32392 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 12675 AN: 25564

East Asian (EAS) AF: 0.637 AC: 25024 AN: 39310

South Asian (SAS) AF: 0.573 AC: 47963 AN: 83746

European-Finnish (FIN) AF: 0.584 AC: 31171 AN: 53358

Middle Eastern (MID) AF: 0.480 AC: 2670 AN: 5560

European-Non Finnish (NFE) AF: 0.568 AC: 584814 AN: 1030088

Other (OTH) AF: 0.560 AC: 32135 AN: 57334

GnomAD4 genome AF: 0.553 AC: 83968 AN: 151830 Hom.: 23527 Cov.: 31 AF XY: 0.555 AC XY: 41161 AN XY: 74200

African (AFR) AF: 0.504 AC: 20853 AN: 41366

American (AMR) AF: 0.624 AC: 9539 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1693 AN: 3470

East Asian (EAS) AF: 0.634 AC: 3271 AN: 5160

South Asian (SAS) AF: 0.548 AC: 2630 AN: 4796

European-Finnish (FIN) AF: 0.586 AC: 6170 AN: 10530

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38112 AN: 67922

Other (OTH) AF: 0.539 AC: 1135 AN: 2106

Alfa AF: 0.559 Hom.: 63867

Bravo AF: 0.558

Asia WGS AF: 0.542 AC: 1885 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.82
CADD	Benign	1.5
DANN	Benign	0.63
PhyloP100		-0.27
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: rs2073425; hg19: chr21-38302769; COSMIC: COSV60796212; COSMIC: COSV60796212;