NM_001352514.2:c.2341G>T

Variant names:

• chr21-36756651-C-A
• NM_001352514.2:c.2341G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001352514.2(HLCS):​c.2341G>T​(p.Asp781Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,882 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.16

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 21-36756651-C-A is Pathogenic according to our data. Variant chr21-36756651-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2676009.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.2341G>T	p.Asp781Tyr	missense_variant	Exon 10 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.2341G>T	p.Asp781Tyr	missense_variant	Exon 10 of 11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 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: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holocarboxylase synthetase deficiency Pathogenic:1

Nov 08, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;D;D
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;.;.
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.1	M;M;M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	.;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	.;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.94
MutPred		0.59		Gain of MoRF binding (P = 0.0505);Gain of MoRF binding (P = 0.0505);Gain of MoRF binding (P = 0.0505);
MVP		0.98
MPC		0.64
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.34
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-38128952;