1-23817442-A-G

Variant names:

• chr1-23817442-A-G
• rs2076344
• NM_000191.3:c.252+34T>C

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.17
• Publications: 7 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, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCL	NM_000191.3	MANE Select	c.252+34T>C		intron	N/A	NP_000182.2
	HMGCL	NM_001166059.2		c.252+34T>C		intron	N/A	NP_001159531.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCL	ENST00000374490.8	TSL:1 MANE Select	c.252+34T>C		intron	N/A	ENSP00000363614.3
	HMGCL	ENST00000509389.5	TSL:1	n.264+34T>C		intron	N/A
	HMGCL	ENST00000436439.6	TSL:2	c.252+34T>C		intron	N/A	ENSP00000389281.2

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140473 AN: 152164 Hom.: 64954 Cov.: 32

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

GnomAD2 exomes AF: 0.902 AC: 225977 AN: 250400 AF XY: 0.901

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 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.: 15 AF XY: 0.910 AC XY: 506297 AN XY: 556140

African (AFR) AF: 0.968 AC: 25256 AN: 26098

American (AMR) AF: 0.893 AC: 39396 AN: 44106

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 20771 AN: 23836

East Asian (EAS) AF: 0.826 AC: 31317 AN: 37926

South Asian (SAS) AF: 0.881 AC: 69239 AN: 78606

European-Finnish (FIN) AF: 0.958 AC: 50994 AN: 53204

Middle Eastern (MID) AF: 0.941 AC: 4749 AN: 5048

European-Non Finnish (NFE) AF: 0.916 AC: 701501 AN: 765548

Other (OTH) AF: 0.909 AC: 43509 AN: 47866

GnomAD4 genome AF: 0.923 AC: 140578 AN: 152282 Hom.: 64996 Cov.: 32 AF XY: 0.923 AC XY: 68755 AN XY: 74452

African (AFR) AF: 0.966 AC: 40136 AN: 41558

American (AMR) AF: 0.888 AC: 13594 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 3015 AN: 3472

East Asian (EAS) AF: 0.791 AC: 4103 AN: 5184

South Asian (SAS) AF: 0.867 AC: 4186 AN: 4828

European-Finnish (FIN) AF: 0.964 AC: 10223 AN: 10600

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.915 AC: 62229 AN: 68024

Other (OTH) AF: 0.918 AC: 1936 AN: 2110

Alfa AF: 0.911 Hom.: 22674

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

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Deficiency of hydroxymethylglutaryl-CoA lyase Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.68
PhyloP100		-1.2
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: rs2076344; hg19: chr1-24143932;