6-55495553-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001042406.2(HMGCLL1):​c.661A>G​(p.Ile221Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,613,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: HMGCLL1 NM_001042406.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3463623).

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>G	p.Ile221Val	missense	Exon 7 of 9	NP_001035865.1	Q8TB92-2
	HMGCLL1	NM_019036.3		c.751A>G	p.Ile251Val	missense	Exon 8 of 10	NP_061909.2	Q8TB92-1
	HMGCLL1	NM_001287741.2		c.565A>G	p.Ile189Val	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>G	p.Ile221Val	missense	Exon 7 of 9	ENSP00000274901.4	Q8TB92-2
	HMGCLL1	ENST00000398661.6	TSL:2	c.751A>G	p.Ile251Val	missense	Exon 8 of 10	ENSP00000381654.2	Q8TB92-1
	HMGCLL1	ENST00000957849.1		c.661A>G	p.Ile221Val	missense	Exon 7 of 9	ENSP00000627908.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249274 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 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: 0.0000252 AC: 1 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: 0.0000558 AC: 62 AN: 1111548

Other (OTH) AF: 0.0000331 AC: 2 AN: 60376

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	2.0	M
PhyloP100		4.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.43
Sift	Benign	0.045	D
Sift4G	Uncertain	0.032	D
Polyphen		0.027	B
Vest4		0.30
MVP		0.35
MPC		0.021
ClinPred		0.29	T
GERP RS		3.2
Varity_R		0.086
gMVP		0.64
Mutation Taster		=82/18	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; COSMIC: COSV104573341;