chr6-55435732-C-G

Variant names:

• chr6-55435732-C-G
• rs373467937
• NM_001042406.2:c.953G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001042406.2(HMGCLL1):​c.953G>C​(p.Gly318Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,603,102 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G318V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HMGCLL1 NM_001042406.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.953G>C	p.Gly318Ala	missense	Exon 9 of 9	NP_001035865.1	Q8TB92-2
	HMGCLL1	NM_019036.3		c.1043G>C	p.Gly348Ala	missense	Exon 10 of 10	NP_061909.2	Q8TB92-1
	HMGCLL1	NM_001287741.2		c.857G>C	p.Gly286Ala	missense	Exon 8 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.953G>C	p.Gly318Ala	missense	Exon 9 of 9	ENSP00000274901.4	Q8TB92-2
	HMGCLL1	ENST00000398661.6	TSL:2	c.1043G>C	p.Gly348Ala	missense	Exon 10 of 10	ENSP00000381654.2	Q8TB92-1
	HMGCLL1	ENST00000957849.1		c.974G>C	p.Gly325Ala	missense	Exon 9 of 9	ENSP00000627908.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151904 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451198 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721784

African (AFR) AF: 0.00 AC: 0 AN: 32898

American (AMR) AF: 0.0000227 AC: 1 AN: 43964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25800

East Asian (EAS) AF: 0.00 AC: 0 AN: 39222

South Asian (SAS) AF: 0.00 AC: 0 AN: 85382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105282

Other (OTH) AF: 0.00 AC: 0 AN: 59838

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151904 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74158

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.0000658 AC: 1 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.83
Sift	Benign	0.050	D
Sift4G	Benign	0.17	T
Polyphen		0.98	D
Vest4		0.57
MutPred		0.60		Gain of helix (P = 0.0022)
MVP		0.83
MPC		0.18
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.90
Mutation Taster		=41/59	disease causing

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: rs373467937; hg19: chr6-55300530;