rs369514739

Variant names:

• chr1-23802174-C-A
• rs369514739
• NM_000191.3:c.*289G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-23802174-C-A
• chr1-23802174-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000191.3(HMGCL):​c.*289G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 593,222 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: HMGCL NM_000191.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.99
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-23802174-C-A is Benign according to our data. Variant chr1-23802174-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 296844.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000453 (69/152330) while in subpopulation SAS AF = 0.0118 (57/4830). AF 95% confidence interval is 0.00935. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.*289G>T		3_prime_UTR	Exon 9 of 9	NP_000182.2	P35914-1
	HMGCL	NM_001166059.2		c.*289G>T		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.*289G>T		3_prime_UTR	Exon 9 of 9	ENSP00000363614.3	P35914-1
	HMGCL	ENST00000892104.1		c.*289G>T		3_prime_UTR	Exon 10 of 10	ENSP00000562163.1
	HMGCL	ENST00000892105.1		c.*289G>T		3_prime_UTR	Exon 9 of 9	ENSP00000562164.1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00106 AC: 466 AN: 440892 Hom.: 4 Cov.: 0 AF XY: 0.00149 AC XY: 345 AN XY: 231248

African (AFR) AF: 0.00 AC: 0 AN: 12348

American (AMR) AF: 0.00 AC: 0 AN: 18480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13592

East Asian (EAS) AF: 0.00 AC: 0 AN: 31102

South Asian (SAS) AF: 0.00958 AC: 407 AN: 42464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29410

Middle Eastern (MID) AF: 0.000511 AC: 1 AN: 1958

European-Non Finnish (NFE) AF: 0.000143 AC: 38 AN: 265774

Other (OTH) AF: 0.000776 AC: 20 AN: 25764

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50 AN XY: 74492

African (AFR) AF: 0.0000962 AC: 4 AN: 41580

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000132

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Deficiency of hydroxymethylglutaryl-CoA lyase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.64
PhyloP100		-3.0
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: rs369514739; hg19: chr1-24128664;