21-36938883-T-G

Variant names:

• chr21-36938883-T-G
• rs764841449
• NM_001352514.2:c.442A>C

Variant summary

Our verdict is Uncertain significance. The variant received 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M148V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HLCS NM_001352514.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.99
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• holocarboxylase synthetase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.442A>C	p.Met148Leu	missense_variant	Exon 3 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.442A>C	p.Met148Leu	missense_variant	Exon 3 of 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: no assertion criteria provided

Submissions by phenotype

Holocarboxylase synthetase deficiency Uncertain:1

Jun 04, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
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
MutationAssessor	Benign	0.0	.;.;.;.;.;.
PhyloP100		2.0
PROVEAN	Benign	0.0	.;N;N;N;.;N
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;T;T;T;.;T
Sift4G	Benign	0.41	T;T;T;.;.;T
Vest4		0.29
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.21
gMVP		0.10
Mutation Taster		=55/145	disease causing

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

Other links and lift over

dbSNP: rs764841449; hg19: chr21-38311183;