rs61732507

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001352514.2(HLCS):c.2361C>T(p.Val787Val) 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 (★★).

Frequency

Genomes: 𝑓 0.019 ( 66 hom., cov: 31)

Exomes 𝑓: 0.0074 ( 85 hom. )

Consequence

HLCS
NM_001352514.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.67

Variant links:

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 links:

HLCS (HGNC:):

HLCS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2 linkuse as main transcript	c.2361C>T	p.Val787Val	synonymous_variant	10/11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3 linkuse as main transcript	c.2361C>T	p.Val787Val	synonymous_variant	10/11		NM_001352514.2	ENSP00000502087.2		P50747-2A0A8C8QSB1

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2920

AN:

152078

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00889

AC XY:

1209

AN XY:

135920

show subpopulations

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.:

Cov.:

AF XY:

0.00742

AC XY:

5398

AN XY:

727238

show subpopulations

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.:

Cov.:

AF XY:

0.0186

AC XY:

1387

AN XY:

74402

show subpopulations

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.:

Bravo

AF:

0.0213

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00573

EpiControl

AF:

0.00504

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holocarboxylase synthetase deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over