rs773398782

chr21-36765148-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001352514.2(HLCS):c.1985G>A(p.Ser662Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.28

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001352514.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 21-36765148-C-T is Pathogenic according to our data. Variant chr21-36765148-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428585.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLCS	NM_001352514.2	c.1985G>A	p.Ser662Asn	missense_variant	8/11	ENST00000674895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLCS	ENST00000674895.3	c.1985G>A	p.Ser662Asn	missense_variant	8/11		NM_001352514.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251456 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Holocarboxylase synthetase deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital	Jun 17, 2017	the patient carry compound heterozygote mutation, one is confirmed to be pathogenic. [c.1522C>T (p.Arg508Trp)]+[ c.1544G>A(p.Ser515Asn)] -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 10, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2022

The c.1544G>A (p.S515N) alteration is located in exon 9 (coding exon 6) of the HLCS gene. This alteration results from a G to A substitution at nucleotide position 1544, causing the serine (S) at amino acid position 515 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;.;.
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
Sift4G	Uncertain	0.015	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.74
MutPred		0.78		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.97
MPC		0.56
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.92

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: rs773398782; hg19: chr21-38137449;