Variant 6-55495429-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001042406.2(HMGCLL1):c.785C>T(p.Thr262Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

HMGCLL1
NM_001042406.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54

Variant links:

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 links:

HMGCLL1 (HGNC:):

HMGCLL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20916808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCLL1	NM_001042406.2 linkuse as main transcript	c.785C>T	p.Thr262Met	missense_variant	7/9	ENST00000274901.9	NP_001035865.1	Q8TB92-2O95896Q9NT06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCLL1	ENST00000274901.9 linkuse as main transcript	c.785C>T	p.Thr262Met	missense_variant	7/9	1	NM_001042406.2	ENSP00000274901.4		Q8TB92-2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000137

AC:

AN:

248740

Hom.:

AF XY:

0.0000963

AC XY:

AN XY:

135006

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000603

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1460988

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000580

Gnomad4 NFE exome

AF:

0.0000702

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000191

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000959

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.875C>T (p.T292M) 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 875, causing the threonine (T) at amino acid position 292 to be replaced by a methionine (M). 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

Benign

0.087

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.58

.;D;D;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.073

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Uncertain

0.066

MutationAssessor

Benign

1.7

.;L;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.018

B;B;B;.

Vest4

0.53

MVP

0.58

MPC

0.056

ClinPred

0.026

GERP RS

3.7

Varity_R

0.061

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over