rs764841449

Positions:

• chr21-36938883-T-G
• chr21-36938883-T-C

Variant summary

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

The NM_001352514.2(HLCS):​c.442A>C​(p.Met148Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.442A>C	p.Met148Leu	missense_variant	3/11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.442A>C	p.Met148Leu	missense_variant	3/11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holocarboxylase synthetase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.14	T;T;T;.;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;.;.;D;T;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T
MetaSVM	Uncertain	0.18	D
PROVEAN	Benign	-0.24	.;N;N;N;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.44	.;T;T;T;.;T
Sift4G	Benign	0.41	T;T;T;.;.;T
Polyphen		0.0010	B;B;B;.;.;.
Vest4		0.29
MutPred		0.55		Loss of disorder (P = 0.1438);Loss of disorder (P = 0.1438);Loss of disorder (P = 0.1438);Loss of disorder (P = 0.1438);.;Loss of disorder (P = 0.1438);
MVP		0.92
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.21
gMVP		0.10

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: rs764841449; hg19: chr21-38311183;