chr21-36937319-C-A

Variant names:

• chr21-36937319-C-A
• rs61732504
• NM_001352514.2:c.567G>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.567G>T​(p.Glu189Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,614,022 control chromosomes in the GnomAD database, including 637 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E189E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (245 hom., cov: 32)
  • Exomes 𝑓: 0.012 (392 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.453
• Publications: 13 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 (MetaRNN=0.0016950369).
• BP6: Variant 21-36937319-C-A is Benign according to our data. Variant chr21-36937319-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.567G>T	p.Glu189Asp	missense_variant	Exon 4 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.567G>T	p.Glu189Asp	missense_variant	Exon 4 of 11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5903 AN: 152100 Hom.: 246 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.0531

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0216 AC: 5374 AN: 248804 AF XY: 0.0212

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00926

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.0383

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.00576

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0116 AC: 16928 AN: 1461804 Hom.: 392 Cov.: 34 AF XY: 0.0124 AC XY: 9051 AN XY: 727194

African (AFR) AF: 0.107 AC: 3591 AN: 33478

American (AMR) AF: 0.00966 AC: 432 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26132

East Asian (EAS) AF: 0.0380 AC: 1509 AN: 39700

South Asian (SAS) AF: 0.0465 AC: 4015 AN: 86254

European-Finnish (FIN) AF: 0.0174 AC: 930 AN: 53362

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5766

European-Non Finnish (NFE) AF: 0.00483 AC: 5366 AN: 1111992

Other (OTH) AF: 0.0160 AC: 966 AN: 60396

GnomAD4 genome AF: 0.0388 AC: 5908 AN: 152218 Hom.: 245 Cov.: 32 AF XY: 0.0394 AC XY: 2930 AN XY: 74420

African (AFR) AF: 0.109 AC: 4513 AN: 41498

American (AMR) AF: 0.0196 AC: 299 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.0361 AC: 187 AN: 5174

South Asian (SAS) AF: 0.0529 AC: 255 AN: 4820

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00591 AC: 402 AN: 68028

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0169 Hom.: 198

Bravo AF: 0.0401

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.104 AC: 458

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.0244 AC: 2958

Asia WGS AF: 0.0470 AC: 163 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Holocarboxylase synthetase deficiency Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.98
DANN	Benign	0.88
DEOGEN2	Benign	0.25	T;T;T;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.61	T;.;.;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.55	N;N;N;.;.;.
PhyloP100		-0.45
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.81	.;N;N;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.36	.;T;T;T;.;T
Sift4G	Benign	0.37	T;T;T;.;.;T
Polyphen		0.16	B;B;B;.;.;.
Vest4		0.015
MutPred		0.14		Loss of glycosylation at P43 (P = 0.1345);Loss of glycosylation at P43 (P = 0.1345);Loss of glycosylation at P43 (P = 0.1345);Loss of glycosylation at P43 (P = 0.1345);.;Loss of glycosylation at P43 (P = 0.1345);
MPC		0.11
ClinPred		0.0040	T
GERP RS		2.5
Varity_R		0.053
gMVP		0.068
Mutation Taster		=96/4	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: rs61732504; hg19: chr21-38309619; COSMIC: COSV60793729;