rs150665851

chr21-36756630-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.957

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 -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 GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.2362G>A	p.Val788Met	missense_variant	10/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.2362G>A	p.Val788Met	missense_variant	10/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152124 Hom.: 2 Cov.: 31

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.: 5 AF XY: 0.00477 AC XY: 648 AN XY: 135922

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.: 20 Cov.: 33 AF XY: 0.00423 AC XY: 3075 AN XY: 727246

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.: 2 Cov.: 31 AF XY: 0.00417 AC XY: 310 AN XY: 74412

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.: 1

Bravo AF: 0.00281

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00479 AC: 581

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not provided Benign:2

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	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	HLCS: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	16
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	N
LIST_S2	Uncertain	0.87	D;.;.
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	0.61	D;D
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs150665851; hg19: chr21-38128931; COSMIC: COSV60794322;