rs1065759

Variant names:

• chr21-36930377-G-A
• rs1065759
• NM_001352514.2:c.1494C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001352514.2(HLCS):​c.1494C>T​(p.Asn498Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,614,184 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (28 hom.)
• Consequence: HLCS NM_001352514.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.395
• Publications: 3 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=-0.67).
• BP6: Variant 21-36930377-G-A is Benign according to our data. Variant chr21-36930377-G-A is described in ClinVar as Benign. ClinVar VariationId is 203767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.395 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00984 (1499/152328) while in subpopulation AFR AF = 0.0343 (1426/41562). AF 95% confidence interval is 0.0328. There are 26 homozygotes in GnomAd4. There are 721 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	NM_001352514.2	MANE Select	c.1494C>T	p.Asn498Asn	synonymous	Exon 5 of 11	NP_001339443.1
	HLCS	NM_000411.8		c.1053C>T	p.Asn351Asn	synonymous	Exon 6 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.1053C>T	p.Asn351Asn	synonymous	Exon 6 of 12	NP_001229713.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	ENST00000674895.3	MANE Select	c.1494C>T	p.Asn498Asn	synonymous	Exon 5 of 11	ENSP00000502087.2
	HLCS	ENST00000336648.8	TSL:1	c.1053C>T	p.Asn351Asn	synonymous	Exon 6 of 12	ENSP00000338387.3
	HLCS	ENST00000399120.5	TSL:1	c.1053C>T	p.Asn351Asn	synonymous	Exon 6 of 12	ENSP00000382071.1

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1500 AN: 152210 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00278 AC: 700 AN: 251484 AF XY: 0.00202

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000967 AC: 1413 AN: 1461856 Hom.: 28 Cov.: 33 AF XY: 0.000822 AC XY: 598 AN XY: 727236

African (AFR) AF: 0.0361 AC: 1208 AN: 33476

American (AMR) AF: 0.00165 AC: 74 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111982

Other (OTH) AF: 0.00166 AC: 100 AN: 60394

GnomAD4 genome AF: 0.00984 AC: 1499 AN: 152328 Hom.: 26 Cov.: 32 AF XY: 0.00968 AC XY: 721 AN XY: 74488

African (AFR) AF: 0.0343 AC: 1426 AN: 41562

American (AMR) AF: 0.00386 AC: 59 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00417 Hom.: 21

Bravo AF: 0.0110

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Holocarboxylase synthetase deficiency (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.6
DANN	Benign	0.51
PhyloP100		0.40
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: rs1065759; hg19: chr21-38302677;