rs140568778

Variant names:

• chr21-36930243-CA-C
• rs140568778
• NM_001352514.2:c.1620+7delT

Your query was ambiguous. Multiple possible variants found:

• chr21-36930243-CA-C
• chr21-36930243-CA-CAA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001352514.2(HLCS):​c.1620+7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,368 control chromosomes in the GnomAD database, including 25,229 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1587 hom., cov: 30)
  • Exomes 𝑓: 0.17 (23642 hom.)
• Consequence: HLCS NM_001352514.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.51
• 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: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 21-36930243-CA-C is Benign according to our data. Variant chr21-36930243-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	NM_001352514.2	MANE Select	c.1620+7delT		splice_region intron	N/A	NP_001339443.1	P50747-2
	HLCS	NM_000411.8		c.1179+7delT		splice_region intron	N/A	NP_000402.3
	HLCS	NM_001242784.3		c.1179+7delT		splice_region intron	N/A	NP_001229713.1	P50747-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.1620+7delT		splice_region intron	N/A	ENSP00000502087.2	P50747-2
	HLCS	ENST00000336648.8	TSL:1	c.1179+7delT		splice_region intron	N/A	ENSP00000338387.3	P50747-1
	HLCS	ENST00000399120.5	TSL:1	c.1179+7delT		splice_region intron	N/A	ENSP00000382071.1	P50747-1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19232 AN: 152114 Hom.: 1588 Cov.: 30

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0994

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0866

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.134 AC: 33730 AN: 251328 AF XY: 0.138

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.00359

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.173 AC: 252293 AN: 1461136 Hom.: 23642 Cov.: 30 AF XY: 0.171 AC XY: 124155 AN XY: 726882

African (AFR) AF: 0.0285 AC: 953 AN: 33470

American (AMR) AF: 0.0789 AC: 3530 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 4766 AN: 26134

East Asian (EAS) AF: 0.00154 AC: 61 AN: 39698

South Asian (SAS) AF: 0.0901 AC: 7775 AN: 86248

European-Finnish (FIN) AF: 0.179 AC: 9576 AN: 53408

Middle Eastern (MID) AF: 0.140 AC: 806 AN: 5766

European-Non Finnish (NFE) AF: 0.194 AC: 215260 AN: 1111324

Other (OTH) AF: 0.158 AC: 9566 AN: 60366

GnomAD4 genome AF: 0.126 AC: 19227 AN: 152232 Hom.: 1587 Cov.: 30 AF XY: 0.123 AC XY: 9184 AN XY: 74432

African (AFR) AF: 0.0353 AC: 1467 AN: 41558

American (AMR) AF: 0.0992 AC: 1517 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 659 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5182

South Asian (SAS) AF: 0.0867 AC: 418 AN: 4822

European-Finnish (FIN) AF: 0.182 AC: 1930 AN: 10600

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12885 AN: 67986

Other (OTH) AF: 0.130 AC: 275 AN: 2110

Alfa AF: 0.164 Hom.: 394

Bravo AF: 0.118

Asia WGS AF: 0.0610 AC: 212 AN: 3478

EpiCase AF: 0.187

EpiControl AF: 0.189

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Holocarboxylase synthetase deficiency (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
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: rs140568778; hg19: chr21-38302543;