6-55495553-T-G

Variant names:

• chr6-55495553-T-G
• rs372806502
• NM_001042406.2:c.661A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001042406.2(HMGCLL1):​c.661A>C​(p.Ile221Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I221T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HMGCLL1 NM_001042406.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042406.2. 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
	HMGCLL1	NM_001042406.2	MANE Select	c.661A>C	p.Ile221Leu	missense	Exon 7 of 9	NP_001035865.1	Q8TB92-2
	HMGCLL1	NM_019036.3		c.751A>C	p.Ile251Leu	missense	Exon 8 of 10	NP_061909.2	Q8TB92-1
	HMGCLL1	NM_001287741.2		c.565A>C	p.Ile189Leu	missense	Exon 6 of 8	NP_001274670.1	Q8TB92-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCLL1	ENST00000274901.9	TSL:1 MANE Select	c.661A>C	p.Ile221Leu	missense	Exon 7 of 9	ENSP00000274901.4	Q8TB92-2
	HMGCLL1	ENST00000398661.6	TSL:2	c.751A>C	p.Ile251Leu	missense	Exon 8 of 10	ENSP00000381654.2	Q8TB92-1
	HMGCLL1	ENST00000957849.1		c.661A>C	p.Ile221Leu	missense	Exon 7 of 9	ENSP00000627908.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111548

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.023
Eigen_PC	Benign	-0.0075
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.019	D
Polyphen		0.39	B
Vest4		0.56
MutPred		0.83		Gain of disorder (P = 0.1232)
MVP		0.54
MPC		0.075
ClinPred		0.94	D
GERP RS		3.2
Varity_R		0.36
gMVP		0.75
Mutation Taster		=78/22	polymorphism

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: rs372806502; hg19: chr6-55360351;