chr1-23825368-C-T

Variant names:

• chr1-23825368-C-T
• rs115611440
• NM_000191.3:c.48G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000191.3(HMGCL):​c.48G>A​(p.Ala16Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,560,010 control chromosomes in the GnomAD database, including 37 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. A16A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (21 hom.)
• Consequence: HMGCL NM_000191.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.219
• Publications: 2 publications found

Genes affected

HMGCL (HGNC:5005): (3-hydroxy-3-methylglutaryl-CoA lyase) The protein encoded by this gene belongs to the HMG-CoA lyase family. It is a mitochondrial enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Mutations in this gene are associated with HMG-CoA lyase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

HMGCL Gene-Disease associations (from GenCC):

• 3-hydroxy-3-methylglutaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen, G2P

LOC105376861 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.042).
• BP6: Variant 1-23825368-C-T is Benign according to our data. Variant chr1-23825368-C-T is described in ClinVar as Benign. ClinVar VariationId is 296855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.219 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00874 (1332/152328) while in subpopulation AFR AF = 0.0267 (1110/41572). AF 95% confidence interval is 0.0254. There are 16 homozygotes in GnomAd4. There are 611 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000191.3. 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
	HMGCL	NM_000191.3	MANE Select	c.48G>A	p.Ala16Ala	synonymous	Exon 1 of 9	NP_000182.2	P35914-1
	HMGCL	NM_001166059.2		c.48G>A	p.Ala16Ala	synonymous	Exon 1 of 7	NP_001159531.1	P35914-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCL	ENST00000374490.8	TSL:1 MANE Select	c.48G>A	p.Ala16Ala	synonymous	Exon 1 of 9	ENSP00000363614.3	P35914-1
	HMGCL	ENST00000509389.5	TSL:1	n.60G>A		non_coding_transcript_exon	Exon 1 of 6
	HMGCL	ENST00000892104.1		c.48G>A	p.Ala16Ala	synonymous	Exon 1 of 10	ENSP00000562163.1

Frequencies

GnomAD3 genomes AF: 0.00871 AC: 1326 AN: 152210 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00314 AC: 512 AN: 162912 AF XY: 0.00253

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00499

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00174 AC: 2456 AN: 1407682 Hom.: 21 Cov.: 32 AF XY: 0.00163 AC XY: 1136 AN XY: 695540

African (AFR) AF: 0.0289 AC: 920 AN: 31854

American (AMR) AF: 0.00600 AC: 224 AN: 37314

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 56 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 36174

South Asian (SAS) AF: 0.000113 AC: 9 AN: 79964

European-Finnish (FIN) AF: 0.0000827 AC: 4 AN: 48390

Middle Eastern (MID) AF: 0.00882 AC: 50 AN: 5666

European-Non Finnish (NFE) AF: 0.000886 AC: 961 AN: 1084788

Other (OTH) AF: 0.00398 AC: 232 AN: 58288

GnomAD4 genome AF: 0.00874 AC: 1332 AN: 152328 Hom.: 16 Cov.: 32 AF XY: 0.00820 AC XY: 611 AN XY: 74490

African (AFR) AF: 0.0267 AC: 1110 AN: 41572

American (AMR) AF: 0.00660 AC: 101 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68030

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00226 Hom.: 3

Bravo AF: 0.0106

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Deficiency of hydroxymethylglutaryl-CoA lyase (5)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		0.22
PromoterAI		-0.20	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115611440; hg19: chr1-24151858;