rs149291867

chr21-36937021-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001352514.2(HLCS):c.865G>A(p.Val289Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,614,110 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (10 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: -1.91

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030751228).
• BP6: Variant 21-36937021-C-T is Benign according to our data. Variant chr21-36937021-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 339966.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000832 (1216/1461884) while in subpopulation MID AF= 0.0052 (30/5768). AF 95% confidence interval is 0.00374. There are 10 homozygotes in gnomad4_exome. There are 610 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.865G>A	p.Val289Ile	missense_variant	4/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.865G>A	p.Val289Ile	missense_variant	4/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152108 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00136 AC: 343 AN: 251400 Hom.: 4 AF XY: 0.00139 AC XY: 189 AN XY: 135882

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000832 AC: 1216 AN: 1461884 Hom.: 10 Cov.: 34 AF XY: 0.000839 AC XY: 610 AN XY: 727240

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152226 Hom.: 1 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74424

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00167 Hom.: 9

Bravo AF: 0.000929

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00101 AC: 123

EpiCase AF: 0.000763

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Holocarboxylase synthetase deficiency Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	HLCS: BS1, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: See above. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HLCS-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	0.86
Dann	Benign	0.89
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.26	T;.;.
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.045
MVP		0.65
MPC		0.099
ClinPred		0.012	T
GERP RS		-6.0
Varity_R		0.023
gMVP		0.10

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: rs149291867; hg19: chr21-38309321;