rs75867009

chr21-36765164-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001352514.2(HLCS):c.1969G>A(p.Gly657Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,204 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G657A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0059 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (10 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.227

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001352514.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.014004856).
• BP6: Variant 21-36765164-C-T is Benign according to our data. Variant chr21-36765164-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00592 (902/152320) while in subpopulation AFR AF= 0.0203 (845/41578). AF 95% confidence interval is 0.0192. There are 14 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.1969G>A	p.Gly657Arg	missense_variant	8/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.1969G>A	p.Gly657Arg	missense_variant	8/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 900 AN: 152202 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00143 AC: 360 AN: 251396 Hom.: 4 AF XY: 0.00111 AC XY: 151 AN XY: 135886

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000625 AC: 913 AN: 1461884 Hom.: 10 Cov.: 32 AF XY: 0.000549 AC XY: 399 AN XY: 727246

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00592 AC: 902 AN: 152320 Hom.: 14 Cov.: 33 AF XY: 0.00565 AC XY: 421 AN XY: 74470

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00109 Hom.: 4

Bravo AF: 0.00691

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 11, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	3.8
Dann	Benign	0.82
DEOGEN2	Pathogenic	0.80	D;D;D
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.62	T;.;.
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.9	M;M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.31
MutPred		0.86		Gain of methylation at G510 (P = 0.0197);Gain of methylation at G510 (P = 0.0197);Gain of methylation at G510 (P = 0.0197);
MVP		0.84
MPC		0.15
ClinPred		0.024	T
GERP RS		-4.1
Varity_R		0.11
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs75867009; hg19: chr21-38137465;