rs61732501

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001352514.2(HLCS):c.1412G>A(p.Arg471His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,160 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R471R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0087 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 109 hom. )

Consequence

HLCS
NM_001352514.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006816119).

BP6

Variant 21-36936474-C-T is Benign according to our data. Variant chr21-36936474-C-T is described in ClinVar as [Benign]. Clinvar id is 137551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36936474-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00872 (1328/152352) while in subpopulation SAS AF= 0.0164 (79/4824). AF 95% confidence interval is 0.0135. There are 7 homozygotes in gnomad4. There are 678 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2 linkuse as main transcript	c.1412G>A	p.Arg471His	missense_variant	4/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3 linkuse as main transcript	c.1412G>A	p.Arg471His	missense_variant	4/11		NM_001352514.2	P4	P50747-2

Frequencies

GnomAD3 genomes

AF:

0.00872

AC:

1327

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.0172

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.0100

AC:

2503

AN:

249592

Hom.:

AF XY:

0.0111

AC XY:

1494

AN XY:

135066

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0163

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0112

AC:

16420

AN:

1461808

Hom.:

109

Cov.:

AF XY:

0.0115

AC XY:

8330

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00483

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0164

Gnomad4 FIN exome

AF:

0.0161

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.0112

GnomAD4 genome

AF:

0.00872

AC:

1328

AN:

152352

Hom.:

Cov.:

AF XY:

0.00910

AC XY:

678

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.00712

Gnomad4 ASJ

AF:

0.00950

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.0172

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00986

Hom.:

Bravo

AF:

0.00741

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.00974

AC:

1182

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0123

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holocarboxylase synthetase deficiency

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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

Oct 25, 2013

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

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.021

DANN

Benign

0.53

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.057

T;.;.

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

-0.51

N;N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

0.46

.;N;N

REVEL

Benign

0.21

Sift

Benign

0.30

.;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.047

MPC

0.15

ClinPred

0.0051

GERP RS

-8.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.32

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