6-55495555-G-A

Position:

• chr6-55495555-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001042406.2(HMGCLL1):​c.659C>T​(p.Thr220Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HMGCLL1 NM_001042406.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.15

Genes affected

HMGCLL1 (HGNC:21359): (3-hydroxy-3-methylglutaryl-CoA lyase like 1) Enables hydroxymethylglutaryl-CoA lyase activity. Involved in ketone body biosynthetic process. Located in several cellular components, including cytosol; endoplasmic reticulum; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

HMGCLL1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCLL1	NM_001042406.2	c.659C>T	p.Thr220Ile	missense_variant	7/9	ENST00000274901.9	NP_001035865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCLL1	ENST00000274901.9	c.659C>T	p.Thr220Ile	missense_variant	7/9	1	NM_001042406.2	ENSP00000274901.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461300 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The c.749C>T (p.T250I) alteration is located in exon 8 (coding exon 8) of the HMGCLL1 gene. This alteration results from a C to T substitution at nucleotide position 749, causing the threonine (T) at amino acid position 250 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	.;D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.6	.;H;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.84
MutPred		0.95		.;Loss of disorder (P = 0.0662);.;.;
MVP		0.82
MPC		0.18
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.86
gMVP		0.97

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: rs1766532028; hg19: chr6-55360353;