21-36754206-T-C

Variant names:

• chr21-36754206-T-C
• rs77014096
• NM_001352514.2:c.*40A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001352514.2(HLCS):​c.*40A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,601,814 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (54 hom., cov: 33)
  • Exomes 𝑓: 0.027 (610 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.28
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-36754206-T-C is Benign according to our data. Variant chr21-36754206-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.021 (3188/151622) while in subpopulation EAS AF = 0.0423 (216/5112). AF 95% confidence interval is 0.0376. There are 54 homozygotes in GnomAd4. There are 1586 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	NM_001352514.2	MANE Select	c.*40A>G		3_prime_UTR	Exon 11 of 11	NP_001339443.1
	HLCS	NM_000411.8		c.*40A>G		3_prime_UTR	Exon 12 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.*40A>G		3_prime_UTR	Exon 12 of 12	NP_001229713.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.*40A>G		3_prime_UTR	Exon 11 of 11	ENSP00000502087.2
	HLCS	ENST00000336648.8	TSL:1	c.*40A>G		3_prime_UTR	Exon 12 of 12	ENSP00000338387.3
	HLCS	ENST00000399120.5	TSL:1	c.*40A>G		3_prime_UTR	Exon 12 of 12	ENSP00000382071.1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3191 AN: 151504 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.00510

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0551

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.0270 AC: 6660 AN: 246708 AF XY: 0.0275

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0233

Gnomad ASJ exome AF: 0.0502

Gnomad EAS exome AF: 0.0423

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0267 AC: 38734 AN: 1450192 Hom.: 610 Cov.: 28 AF XY: 0.0271 AC XY: 19577 AN XY: 721952

African (AFR) AF: 0.00475 AC: 158 AN: 33250

American (AMR) AF: 0.0233 AC: 1039 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 1311 AN: 26036

East Asian (EAS) AF: 0.0353 AC: 1400 AN: 39606

South Asian (SAS) AF: 0.0314 AC: 2691 AN: 85780

European-Finnish (FIN) AF: 0.0170 AC: 891 AN: 52516

Middle Eastern (MID) AF: 0.0493 AC: 271 AN: 5494

European-Non Finnish (NFE) AF: 0.0266 AC: 29311 AN: 1102904

Other (OTH) AF: 0.0277 AC: 1662 AN: 60032

GnomAD4 genome AF: 0.0210 AC: 3188 AN: 151622 Hom.: 54 Cov.: 33 AF XY: 0.0214 AC XY: 1586 AN XY: 74048

African (AFR) AF: 0.00508 AC: 210 AN: 41298

American (AMR) AF: 0.0240 AC: 366 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 191 AN: 3464

East Asian (EAS) AF: 0.0423 AC: 216 AN: 5112

South Asian (SAS) AF: 0.0268 AC: 129 AN: 4806

European-Finnish (FIN) AF: 0.0202 AC: 211 AN: 10446

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0261 AC: 1776 AN: 67944

Other (OTH) AF: 0.0238 AC: 50 AN: 2102

Alfa AF: 0.0261 Hom.: 87

Bravo AF: 0.0215

Asia WGS AF: 0.0240 AC: 85 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Holocarboxylase synthetase deficiency (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.49
DANN	Benign	0.42
PhyloP100		-4.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs77014096; hg19: chr21-38126507;