1-23802359-C-T

Variant names:

• chr1-23802359-C-T
• rs552915017
• NM_000191.3:c.*104G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000191.3(HMGCL):​c.*104G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 821,374 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: HMGCL NM_000191.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.470
• Publications: 0 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: PanelApp Australia, G2P, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00178 (270/151276) while in subpopulation NFE AF = 0.00254 (172/67678). AF 95% confidence interval is 0.00223. There are 0 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 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.*104G>A		3_prime_UTR	Exon 9 of 9	NP_000182.2	P35914-1
	HMGCL	NM_001166059.2		c.*104G>A		3_prime_UTR	Exon 7 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.*104G>A		3_prime_UTR	Exon 9 of 9	ENSP00000363614.3	P35914-1
	HMGCL	ENST00000892104.1		c.*104G>A		3_prime_UTR	Exon 10 of 10	ENSP00000562163.1
	HMGCL	ENST00000892105.1		c.*104G>A		3_prime_UTR	Exon 9 of 9	ENSP00000562164.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 271 AN: 151156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00550

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000840

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00384

GnomAD4 exome AF: 0.00203 AC: 1358 AN: 670098 Hom.: 5 Cov.: 8 AF XY: 0.00198 AC XY: 719 AN XY: 362242

African (AFR) AF: 0.000758 AC: 14 AN: 18466

American (AMR) AF: 0.00293 AC: 126 AN: 42972

Ashkenazi Jewish (ASJ) AF: 0.00453 AC: 96 AN: 21184

East Asian (EAS) AF: 0.00 AC: 0 AN: 36182

South Asian (SAS) AF: 0.000633 AC: 44 AN: 69538

European-Finnish (FIN) AF: 0.000149 AC: 7 AN: 46946

Middle Eastern (MID) AF: 0.00301 AC: 10 AN: 3318

European-Non Finnish (NFE) AF: 0.00247 AC: 979 AN: 396938

Other (OTH) AF: 0.00237 AC: 82 AN: 34554

GnomAD4 genome AF: 0.00178 AC: 270 AN: 151276 Hom.: 0 Cov.: 33 AF XY: 0.00168 AC XY: 124 AN XY: 73934

African (AFR) AF: 0.000753 AC: 31 AN: 41182

American (AMR) AF: 0.00223 AC: 34 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00550 AC: 19 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.000841 AC: 4 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00254 AC: 172 AN: 67678

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00191

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.1
DANN	Benign	0.63
PhyloP100		0.47
Mutation Taster		=99/1	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: rs552915017; hg19: chr1-24128849;