rs192071003

Variant names:

• chr1-23802269-G-C
• rs192071003
• NM_000191.3:c.*194C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000191.3(HMGCL):​c.*194C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 626,058 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (19 hom.)
• Consequence: HMGCL NM_000191.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.209
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-23802269-G-C is Benign according to our data. Variant chr1-23802269-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 296845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00507 (773/152338) while in subpopulation NFE AF = 0.00735 (500/68024). AF 95% confidence interval is 0.00682. There are 8 homozygotes in GnomAd4. There are 398 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.*194C>G		3_prime_UTR	Exon 9 of 9	NP_000182.2	P35914-1
	HMGCL	NM_001166059.2		c.*194C>G		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.*194C>G		3_prime_UTR	Exon 9 of 9	ENSP00000363614.3	P35914-1
	HMGCL	ENST00000892104.1		c.*194C>G		3_prime_UTR	Exon 10 of 10	ENSP00000562163.1
	HMGCL	ENST00000892105.1		c.*194C>G		3_prime_UTR	Exon 9 of 9	ENSP00000562164.1

Frequencies

GnomAD3 genomes AF: 0.00508 AC: 773 AN: 152220 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00596 AC: 2823 AN: 473720 Hom.: 19 Cov.: 3 AF XY: 0.00547 AC XY: 1379 AN XY: 252118

African (AFR) AF: 0.00189 AC: 25 AN: 13204

American (AMR) AF: 0.00171 AC: 40 AN: 23386

Ashkenazi Jewish (ASJ) AF: 0.00305 AC: 45 AN: 14778

East Asian (EAS) AF: 0.00 AC: 0 AN: 31530

South Asian (SAS) AF: 0.00 AC: 0 AN: 48760

European-Finnish (FIN) AF: 0.0174 AC: 536 AN: 30886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2084

European-Non Finnish (NFE) AF: 0.00731 AC: 2060 AN: 281964

Other (OTH) AF: 0.00431 AC: 117 AN: 27128

GnomAD4 genome AF: 0.00507 AC: 773 AN: 152338 Hom.: 8 Cov.: 33 AF XY: 0.00534 AC XY: 398 AN XY: 74496

African (AFR) AF: 0.00118 AC: 49 AN: 41574

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0179 AC: 190 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00735 AC: 500 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00561 Hom.: 1

Bravo AF: 0.00391

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Deficiency of hydroxymethylglutaryl-CoA lyase (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.1
DANN	Benign	0.46
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs192071003; hg19: chr1-24128759; COSMIC: COSV52525366; COSMIC: COSV52525366;