rs61732507

Variant names:

• chr21-36756631-G-A
• rs61732507
• NM_001352514.2:c.2361C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-36756631-G-A
• chr21-36756631-G-C
• chr21-36756631-G-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.2361C>T​(p.Val787Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00853 in 1,614,062 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V787V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (66 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (85 hom.)
• Consequence: HLCS NM_001352514.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.67
• 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: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 21-36756631-G-A is Benign according to our data. Variant chr21-36756631-G-A is described in ClinVar as Benign. ClinVar VariationId is 137546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0193 (2931/152196) while in subpopulation AFR AF = 0.0508 (2110/41502). AF 95% confidence interval is 0.049. There are 66 homozygotes in GnomAd4. There are 1387 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLCS	NM_001352514.2	MANE Select	c.2361C>T	p.Val787Val	synonymous	Exon 10 of 11	NP_001339443.1	P50747-2
	HLCS	NM_000411.8		c.1920C>T	p.Val640Val	synonymous	Exon 11 of 12	NP_000402.3
	HLCS	NM_001242784.3		c.1920C>T	p.Val640Val	synonymous	Exon 11 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.2361C>T	p.Val787Val	synonymous	Exon 10 of 11	ENSP00000502087.2	P50747-2
	HLCS	ENST00000336648.8	TSL:1	c.1920C>T	p.Val640Val	synonymous	Exon 11 of 12	ENSP00000338387.3	P50747-1
	HLCS	ENST00000399120.5	TSL:1	c.1920C>T	p.Val640Val	synonymous	Exon 11 of 12	ENSP00000382071.1	P50747-1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2920 AN: 152078 Hom.: 66 Cov.: 31

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.00938 AC: 2358 AN: 251494 AF XY: 0.00889

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00596

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.00741 AC: 10834 AN: 1461866 Hom.: 85 Cov.: 33 AF XY: 0.00742 AC XY: 5398 AN XY: 727238

African (AFR) AF: 0.0497 AC: 1663 AN: 33480

American (AMR) AF: 0.00758 AC: 339 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 286 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0138 AC: 1191 AN: 86250

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53420

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.00606 AC: 6740 AN: 1111994

Other (OTH) AF: 0.00874 AC: 528 AN: 60394

GnomAD4 genome AF: 0.0193 AC: 2931 AN: 152196 Hom.: 66 Cov.: 31 AF XY: 0.0186 AC XY: 1387 AN XY: 74402

African (AFR) AF: 0.0508 AC: 2110 AN: 41502

American (AMR) AF: 0.0115 AC: 176 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5180

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4816

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00600 AC: 408 AN: 68010

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.0118 Hom.: 23

Bravo AF: 0.0213

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00504

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.0020
DANN	Benign	0.75
PhyloP100		-2.7
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: rs61732507; hg19: chr21-38128932; COSMIC: COSV107408223;