rs1065758

Variant names:

• chr21-36936611-G-A
• rs1065758
• NM_001352514.2:c.1275C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-36936611-G-A
• chr21-36936611-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001352514.2(HLCS):​c.1275C>T​(p.Ser425Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,614,060 control chromosomes in the GnomAD database, including 19,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1279 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18220 hom.)
• Consequence: HLCS NM_001352514.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.689
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-36936611-G-A is Benign according to our data. Variant chr21-36936611-G-A is described in ClinVar as Benign. ClinVar VariationId is 92916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.689 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.1275C>T	p.Ser425Ser	synonymous_variant	Exon 4 of 11	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.1275C>T	p.Ser425Ser	synonymous_variant	Exon 4 of 11		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17769 AN: 152086 Hom.: 1280 Cov.: 32

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0846

Gnomad ASJ AF: 0.0994

Gnomad EAS AF: 0.0486

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.119 AC: 30006 AN: 251134 AF XY: 0.121

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.0632

Gnomad ASJ exome AF: 0.0982

Gnomad EAS exome AF: 0.0480

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.153 AC: 223330 AN: 1461856 Hom.: 18220 Cov.: 35 AF XY: 0.151 AC XY: 109543 AN XY: 727230

African (AFR) AF: 0.0429 AC: 1437 AN: 33480

American (AMR) AF: 0.0663 AC: 2967 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2613 AN: 26136

East Asian (EAS) AF: 0.0511 AC: 2029 AN: 39700

South Asian (SAS) AF: 0.0670 AC: 5777 AN: 86258

European-Finnish (FIN) AF: 0.172 AC: 9186 AN: 53414

Middle Eastern (MID) AF: 0.0818 AC: 472 AN: 5768

European-Non Finnish (NFE) AF: 0.171 AC: 190657 AN: 1111980

Other (OTH) AF: 0.136 AC: 8192 AN: 60396

GnomAD4 genome AF: 0.117 AC: 17763 AN: 152204 Hom.: 1279 Cov.: 32 AF XY: 0.114 AC XY: 8495 AN XY: 74428

African (AFR) AF: 0.0472 AC: 1961 AN: 41542

American (AMR) AF: 0.0844 AC: 1291 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0994 AC: 345 AN: 3472

East Asian (EAS) AF: 0.0487 AC: 252 AN: 5170

South Asian (SAS) AF: 0.0618 AC: 298 AN: 4822

European-Finnish (FIN) AF: 0.176 AC: 1866 AN: 10598

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11463 AN: 67988

Other (OTH) AF: 0.112 AC: 237 AN: 2108

Alfa AF: 0.147 Hom.: 6533

Bravo AF: 0.108

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.165

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holocarboxylase synthetase deficiency Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 21, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.89
DANN	Benign	0.43
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1065758; hg19: chr21-38308911; COSMIC: COSV60793855; COSMIC: COSV60793855;