21-36756558-G-T

Variant names:

• chr21-36756558-G-T
• rs146448211
• NM_001352514.2:c.2434C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001352514.2(HLCS):​c.2434C>A​(p.Arg812Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000659 in 151,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R812R) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: HLCS NM_001352514.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.64
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352514.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	NM_001352514.2	MANE Select	c.2434C>A	p.Arg812Arg	synonymous	Exon 10 of 11	NP_001339443.1
	HLCS	NM_000411.8		c.1993C>A	p.Arg665Arg	synonymous	Exon 11 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.1993C>A	p.Arg665Arg	synonymous	Exon 11 of 12	NP_001229713.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.2434C>A	p.Arg812Arg	synonymous	Exon 10 of 11	ENSP00000502087.2
	HLCS	ENST00000336648.8	TSL:1	c.1993C>A	p.Arg665Arg	synonymous	Exon 11 of 12	ENSP00000338387.3
	HLCS	ENST00000399120.5	TSL:1	c.1993C>A	p.Arg665Arg	synonymous	Exon 11 of 12	ENSP00000382071.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151536 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151648 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74098

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67900

Other (OTH) AF: 0.00 AC: 0 AN: 2100

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.4
DANN	Benign	0.81
PhyloP100		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146448211; hg19: chr21-38128859;