rs11701035

Variant names:

• chr21-36868670-G-A
• rs11701035
• NM_001352514.2:c.1892+28190C>T

Variant summary

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

The NM_001352514.2(HLCS):​c.1892+28190C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 151,696 control chromosomes in the GnomAD database, including 3,084 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 0.20 (3084 hom., cov: 31)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 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.1892+28190C>T		intron	N/A	NP_001339443.1	P50747-2
	HLCS	NM_000411.8		c.1451+28190C>T		intron	N/A	NP_000402.3
	HLCS	NM_001242784.3		c.1451+28190C>T		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.1892+28190C>T		intron	N/A	ENSP00000502087.2	P50747-2
	HLCS	ENST00000336648.8	TSL:1	c.1451+28190C>T		intron	N/A	ENSP00000338387.3	P50747-1
	HLCS	ENST00000399120.5	TSL:1	c.1451+28190C>T		intron	N/A	ENSP00000382071.1	P50747-1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29641 AN: 151580 Hom.: 3078 Cov.: 31

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0819

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.196 AC: 29669 AN: 151696 Hom.: 3084 Cov.: 31 AF XY: 0.191 AC XY: 14189 AN XY: 74120

African (AFR) AF: 0.236 AC: 9741 AN: 41342

American (AMR) AF: 0.215 AC: 3280 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 724 AN: 3466

East Asian (EAS) AF: 0.150 AC: 775 AN: 5162

South Asian (SAS) AF: 0.176 AC: 845 AN: 4800

European-Finnish (FIN) AF: 0.0819 AC: 858 AN: 10480

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12485 AN: 67886

Other (OTH) AF: 0.220 AC: 464 AN: 2110

Alfa AF: 0.192 Hom.: 3715

Bravo AF: 0.204

Asia WGS AF: 0.166 AC: 582 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		0.022
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11701035; hg19: chr21-38240970;