rs150665851

Positions:

chr21-36756630-C-T

Variant summary

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

The NM_001352514.2(HLCS):c.2362G>A(p.Val788Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,614,128 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0043 ( 20 hom. )

Consequence

HLCS
NM_001352514.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.957

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=0.009711772).

BP6

Variant 21-36756630-C-T is Benign according to our data. Variant chr21-36756630-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 203755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-36756630-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (572/152242) while in subpopulation NFE AF= 0.00448 (305/68034). AF 95% confidence interval is 0.00407. There are 2 homozygotes in gnomad4. There are 310 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2 linkuse as main transcript	c.2362G>A	p.Val788Met	missense_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.2362G>A	p.Val788Met	missense_variant	10/11		NM_001352514.2	ENSP00000502087	P4	P50747-2

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00448

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00449

AC:

1129

AN:

251496

Hom.:

AF XY:

0.00477

AC XY:

648

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00863

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.0131

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00423

GnomAD4 exome

AF:

0.00428

AC:

6251

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00423

AC XY:

3075

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.00903

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00298

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.00417

Gnomad4 OTH exome

AF:

0.00402

GnomAD4 genome

AF:

0.00376

AC:

572

AN:

152242

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

310

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000747

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0119

Gnomad4 NFE

AF:

0.00448

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00397

Hom.:

Bravo

AF:

0.00281

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00479

AC:

581

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	HLCS: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Holocarboxylase synthetase deficiency

Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.87

D;.;.

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.9

L;L;L

MutationTaster

Benign

0.61

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

.;N;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

.;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.62

P;P;P

Vest4

0.63

MVP

0.93

MPC

0.23

ClinPred

0.0065

GERP RS

1.6

Varity_R

0.066

gMVP

0.65

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