1-23802125-C-T

Variant names:

• chr1-23802125-C-T
• rs988536831
• NM_000191.3:c.*338G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000191.3(HMGCL):​c.*338G>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 0.00000248 in 403,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: HMGCL NM_000191.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.141
• 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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*338G>A		3_prime_UTR	Exon 9 of 9	NP_000182.2	P35914-1
	HMGCL	NM_001166059.2		c.*338G>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.*338G>A		3_prime_UTR	Exon 9 of 9	ENSP00000363614.3	P35914-1
	HMGCL	ENST00000892104.1		c.*338G>A		3_prime_UTR	Exon 10 of 10	ENSP00000562163.1
	HMGCL	ENST00000892105.1		c.*338G>A		3_prime_UTR	Exon 9 of 9	ENSP00000562164.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000248 AC: 1 AN: 403510 Hom.: 0 Cov.: 0 AF XY: 0.00000477 AC XY: 1 AN XY: 209828

African (AFR) AF: 0.00 AC: 0 AN: 11956

American (AMR) AF: 0.00 AC: 0 AN: 16186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12806

East Asian (EAS) AF: 0.00 AC: 0 AN: 30264

South Asian (SAS) AF: 0.0000305 AC: 1 AN: 32826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1852

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 245928

Other (OTH) AF: 0.00 AC: 0 AN: 24120

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.70
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs988536831; hg19: chr1-24128615;