rs11714

Variant names:

• chr1-23801977-C-T
• rs11714
• NM_000191.3:c.*486G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000191.3(HMGCL):​c.*486G>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 0.91 in 417,798 control chromosomes in the GnomAD database, including 173,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63512 hom., cov: 35)
  • Exomes 𝑓: 0.91 (109532 hom.)
• Consequence: HMGCL NM_000191.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.918
• Publications: 19 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-23801977-C-T is Benign according to our data. Variant chr1-23801977-C-T is described in ClinVar as Benign. ClinVar VariationId is 296841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

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.*486G>A		3_prime_UTR	Exon 9 of 9	NP_000182.2	P35914-1
	HMGCL	NM_001166059.2		c.*486G>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.*486G>A		3_prime_UTR	Exon 9 of 9	ENSP00000363614.3	P35914-1
	HMGCL	ENST00000892104.1		c.*486G>A		3_prime_UTR	Exon 10 of 10	ENSP00000562163.1
	HMGCL	ENST00000892105.1		c.*486G>A		3_prime_UTR	Exon 9 of 9	ENSP00000562164.1

Frequencies

GnomAD3 genomes AF: 0.913 AC: 138972 AN: 152206 Hom.: 63472 Cov.: 35

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.969

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.873

Gnomad FIN AF: 0.964

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.914

Gnomad OTH AF: 0.920

GnomAD4 exome AF: 0.908 AC: 240948 AN: 265474 Hom.: 109532 Cov.: 0 AF XY: 0.907 AC XY: 122184 AN XY: 134708

African (AFR) AF: 0.931 AC: 7143 AN: 7674

American (AMR) AF: 0.889 AC: 9384 AN: 10558

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 8230 AN: 9458

East Asian (EAS) AF: 0.868 AC: 21274 AN: 24514

South Asian (SAS) AF: 0.877 AC: 5049 AN: 5756

European-Finnish (FIN) AF: 0.958 AC: 20272 AN: 21168

Middle Eastern (MID) AF: 0.933 AC: 1245 AN: 1334

European-Non Finnish (NFE) AF: 0.911 AC: 152862 AN: 167826

Other (OTH) AF: 0.901 AC: 15489 AN: 17186

GnomAD4 genome AF: 0.913 AC: 139074 AN: 152324 Hom.: 63512 Cov.: 35 AF XY: 0.914 AC XY: 68077 AN XY: 74492

African (AFR) AF: 0.929 AC: 38616 AN: 41574

American (AMR) AF: 0.878 AC: 13442 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 3005 AN: 3472

East Asian (EAS) AF: 0.831 AC: 4295 AN: 5168

South Asian (SAS) AF: 0.873 AC: 4220 AN: 4832

European-Finnish (FIN) AF: 0.964 AC: 10241 AN: 10618

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.914 AC: 62176 AN: 68040

Other (OTH) AF: 0.913 AC: 1931 AN: 2114

Alfa AF: 0.909 Hom.: 104614

Bravo AF: 0.909

Asia WGS AF: 0.842 AC: 2928 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Deficiency of hydroxymethylglutaryl-CoA lyase (1)
-	-	1	not provided (1)
-	-	1	UDPglucose-4-epimerase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.0
DANN	Benign	0.81
PhyloP100		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs11714; hg19: chr1-24128467;