rs61732507

chr21-36756631-G-Achr21-36756631-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001352514.2(HLCS):c.2361C>T(p.Val787=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00853 in 1,614,062 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V787V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (66 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (85 hom.)
• Consequence: HLCS NM_001352514.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.67

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 21-36756631-G-A is Benign according to our data. Variant chr21-36756631-G-A is described in ClinVar as [Benign]. Clinvar id is 137546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36756631-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0193 (2931/152196) while in subpopulation AFR AF= 0.0508 (2110/41502). AF 95% confidence interval is 0.049. There are 66 homozygotes in gnomad4. There are 1387 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.2361C>T	p.Val787=	synonymous_variant	10/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.2361C>T	p.Val787=	synonymous_variant	10/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2920 AN: 152078 Hom.: 66 Cov.: 31

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.00938 AC: 2358 AN: 251494 Hom.: 41 AF XY: 0.00889 AC XY: 1209 AN XY: 135920

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0146

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00596

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.00741 AC: 10834 AN: 1461866 Hom.: 85 Cov.: 33 AF XY: 0.00742 AC XY: 5398 AN XY: 727238

Gnomad4 AFR exome AF: 0.0497

Gnomad4 AMR exome AF: 0.00758

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0138

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00606

Gnomad4 OTH exome AF: 0.00874

GnomAD4 genome AF: 0.0193 AC: 2931 AN: 152196 Hom.: 66 Cov.: 31 AF XY: 0.0186 AC XY: 1387 AN XY: 74402

Gnomad4 AFR AF: 0.0508

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00600

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0117 Hom.: 16

Bravo AF: 0.0213

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00504

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.0020
Dann	Benign	0.75

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: rs61732507; hg19: chr21-38128932;