Variant 1-23817442-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000191.3(HMGCL):c.252+34T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,234,520 control chromosomes in the GnomAD database, including 515,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.92 ( 64996 hom., cov: 32)

Exomes 𝑓: 0.91 ( 450455 hom. )

Consequence

HMGCL
NM_000191.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.17

Variant links:

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 links:

HMGCL (HGNC:):

HMGCL links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-23817442-A-G is Benign according to our data. Variant chr1-23817442-A-G is described in ClinVar as [Benign]. Clinvar id is 255488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCL	NM_000191.3 linkuse as main transcript	c.252+34T>C		intron_variant		ENST00000374490.8	NP_000182.2	P35914-1
HMGCL	NM_001166059.2 linkuse as main transcript	c.252+34T>C		intron_variant			NP_001159531.1	P35914-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCL	ENST00000374490.8 linkuse as main transcript	c.252+34T>C		intron_variant		1	NM_000191.3	ENSP00000363614.3		P35914-1

Frequencies

GnomAD3 genomes

AF:

0.923

AC:

140473

AN:

152164

Hom.:

64954

Cov.:

show subpopulations

Gnomad AFR

AF:

0.966

Gnomad AMI

AF:

0.967

Gnomad AMR

AF:

0.888

Gnomad ASJ

AF:

0.868

Gnomad EAS

AF:

0.791

Gnomad SAS

AF:

0.867

Gnomad FIN

AF:

0.964

Gnomad MID

AF:

0.930

Gnomad NFE

AF:

0.915

Gnomad OTH

AF:

0.924

GnomAD3 exomes

AF:

0.902

AC:

225977

AN:

250400

Hom.:

102208

AF XY:

0.901

AC XY:

121948

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.968

Gnomad AMR exome

AF:

0.895

Gnomad ASJ exome

AF:

0.869

Gnomad EAS exome

AF:

0.789

Gnomad SAS exome

AF:

0.874

Gnomad FIN exome

AF:

0.960

Gnomad NFE exome

AF:

0.913

Gnomad OTH exome

AF:

0.910

GnomAD4 exome

AF:

0.912

AC:

986732

AN:

1082238

Hom.:

450455

Cov.:

AF XY:

0.910

AC XY:

506297

AN XY:

556140

show subpopulations

Gnomad4 AFR exome

AF:

0.968

Gnomad4 AMR exome

AF:

0.893

Gnomad4 ASJ exome

AF:

0.871

Gnomad4 EAS exome

AF:

0.826

Gnomad4 SAS exome

AF:

0.881

Gnomad4 FIN exome

AF:

0.958

Gnomad4 NFE exome

AF:

0.916

Gnomad4 OTH exome

AF:

0.909

GnomAD4 genome

AF:

0.923

AC:

140578

AN:

152282

Hom.:

64996

Cov.:

AF XY:

0.923

AC XY:

68755

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.966

Gnomad4 AMR

AF:

0.888

Gnomad4 ASJ

AF:

0.868

Gnomad4 EAS

AF:

0.791

Gnomad4 SAS

AF:

0.867

Gnomad4 FIN

AF:

0.964

Gnomad4 NFE

AF:

0.915

Gnomad4 OTH

AF:

0.918

Alfa

AF:

0.919

Hom.:

12463

Bravo

AF:

0.920

Asia WGS

AF:

0.833

AC:

2898

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Deficiency of hydroxymethylglutaryl-CoA lyase

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.3

DANN

Benign

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over