21-36751019-CAA-CA

Variant names:

• chr21-36751019-CA-C
• rs35955622
• NM_001352514.2:c.*3226delT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001352514.2(HLCS):​c.*3226delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 139,370 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 30)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: HLCS NM_001352514.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.208
• 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: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00263 (366/139302) while in subpopulation NFE AF = 0.00327 (209/63842). AF 95% confidence interval is 0.00291. There are 1 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*3226delT		3_prime_UTR	Exon 11 of 11	NP_001339443.1	P50747-2
	HLCS	NM_000411.8		c.*3226delT		3_prime_UTR	Exon 12 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.*3226delT		3_prime_UTR	Exon 12 of 12	NP_001229713.1	P50747-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.*3226delT		3_prime_UTR	Exon 11 of 11	ENSP00000502087.2	P50747-2
	HLCS	ENST00000336648.8	TSL:1	c.*3226delT		3_prime_UTR	Exon 12 of 12	ENSP00000338387.3	P50747-1
	HLCS	ENST00000612277.4	TSL:5	c.*3226delT		3_prime_UTR	Exon 12 of 12	ENSP00000479939.1	P50747-1

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 363 AN: 139248 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00284

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00327

Gnomad OTH AF: 0.00264

GnomAD4 exome AF: 0.0147 AC: 1 AN: 68 Hom.: 0 Cov.: 0 AF XY: 0.0294 AC XY: 1 AN XY: 34

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0147 AC: 1 AN: 68

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00263 AC: 366 AN: 139302 Hom.: 1 Cov.: 30 AF XY: 0.00256 AC XY: 172 AN XY: 67284

African (AFR) AF: 0.00268 AC: 102 AN: 38072

American (AMR) AF: 0.00108 AC: 15 AN: 13924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3312

East Asian (EAS) AF: 0.00285 AC: 14 AN: 4912

South Asian (SAS) AF: 0.00187 AC: 8 AN: 4270

European-Finnish (FIN) AF: 0.00152 AC: 12 AN: 7920

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.00327 AC: 209 AN: 63842

Other (OTH) AF: 0.00263 AC: 5 AN: 1904

Alfa AF: 0.000138 Hom.: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Holocarboxylase synthetase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

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: rs35955622; hg19: chr21-38123320; COSMIC: COSV51767439; COSMIC: COSV51767439;