1-23801977-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCL	NM_000191.3	c.*486G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000374490.8	NP_000182.2
HMGCL	NM_001166059.2	c.*486G>A		3_prime_UTR_variant	Exon 7 of 7		NP_001159531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCL	ENST00000374490	c.*486G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_000191.3	ENSP00000363614.3
HMGCL	ENST00000436439	c.*486G>A		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000389281.2
HMGCL	ENST00000235958	c.*486G>A		3_prime_UTR_variant	Exon 5 of 5	5		ENSP00000235958.4
HMGCL	ENST00000374487.6	n.2061G>A		non_coding_transcript_exon_variant	Exon 10 of 10	2

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

Gnomad4 AFR exome AF: 0.931

Gnomad4 AMR exome AF: 0.889

Gnomad4 ASJ exome AF: 0.870

Gnomad4 EAS exome AF: 0.868

Gnomad4 SAS exome AF: 0.877

Gnomad4 FIN exome AF: 0.958

Gnomad4 NFE exome AF: 0.911

Gnomad4 OTH exome AF: 0.901

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

Gnomad4 AFR AF: 0.929

Gnomad4 AMR AF: 0.878

Gnomad4 ASJ AF: 0.865

Gnomad4 EAS AF: 0.831

Gnomad4 SAS AF: 0.873

Gnomad4 FIN AF: 0.964

Gnomad4 NFE AF: 0.914

Gnomad4 OTH AF: 0.913

Alfa AF: 0.908 Hom.: 82618

Bravo AF: 0.909

Asia WGS AF: 0.842 AC: 2928 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

UDPglucose-4-epimerase deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.0
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs11714; hg19: chr1-24128467;