chr21-36936972-G-C

Position:

• chr21-36936972-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001352514.2(HLCS):​c.914C>G​(p.Thr305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.540

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09187111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.914C>G	p.Thr305Arg	missense_variant	4/11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.914C>G	p.Thr305Arg	missense_variant	4/11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	5.6
DANN	Benign	0.88
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.82	T;.;.
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.82	.;N;N
REVEL	Benign	0.23
Sift	Benign	0.41	.;T;T
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.011	B;B;B
Vest4		0.14
MutPred		0.32		Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);
MVP		0.85
MPC		0.30
ClinPred		0.035	T
GERP RS		-2.0
Varity_R		0.059
gMVP		0.30

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: rs112176097; hg19: chr21-38309272;