chr21-36817196-A-G

Variant names:

• chr21-36817196-A-G
• rs2835468
• NM_001352514.2:c.1893-49911T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001352514.2(HLCS):​c.1893-49911T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 152,146 control chromosomes in the GnomAD database, including 7,565 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7565 hom., cov: 32)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.463
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

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.1893-49911T>C		intron	N/A	NP_001339443.1
	HLCS	NM_000411.8		c.1452-49911T>C		intron	N/A	NP_000402.3
	HLCS	NM_001242784.3		c.1452-49911T>C		intron	N/A	NP_001229713.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.1893-49911T>C		intron	N/A	ENSP00000502087.2
	HLCS	ENST00000336648.8	TSL:1	c.1452-49911T>C		intron	N/A	ENSP00000338387.3
	HLCS	ENST00000399120.5	TSL:1	c.1452-49911T>C		intron	N/A	ENSP00000382071.1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46553 AN: 152028 Hom.: 7555 Cov.: 32

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.0788

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.320

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.306 AC: 46603 AN: 152146 Hom.: 7565 Cov.: 32 AF XY: 0.300 AC XY: 22356 AN XY: 74410

African (AFR) AF: 0.377 AC: 15637 AN: 41480

American (AMR) AF: 0.227 AC: 3472 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 825 AN: 3472

East Asian (EAS) AF: 0.0782 AC: 406 AN: 5190

South Asian (SAS) AF: 0.242 AC: 1170 AN: 4826

European-Finnish (FIN) AF: 0.259 AC: 2743 AN: 10594

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21290 AN: 67962

Other (OTH) AF: 0.319 AC: 674 AN: 2114

Alfa AF: 0.307 Hom.: 2950

Bravo AF: 0.305

Asia WGS AF: 0.184 AC: 639 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.34
DANN	Benign	0.24
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs2835468; hg19: chr21-38189496;