chr6-55514076-C-T

Position:

• chr6-55514076-C-T

Variant summary

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

The NM_001042406.2(HMGCLL1):​c.514G>A​(p.Ala172Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HMGCLL1 NM_001042406.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06

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

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, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCLL1	NM_001042406.2	c.514G>A	p.Ala172Thr	missense_variant	5/9	ENST00000274901.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCLL1	ENST00000274901.9	c.514G>A	p.Ala172Thr	missense_variant	5/9	1	NM_001042406.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Mar 31, 2023

The c.604G>A (p.A202T) alteration is located in exon 6 (coding exon 6) of the HMGCLL1 gene. This alteration results from a G to A substitution at nucleotide position 604, causing the alanine (A) at amino acid position 202 to be replaced by a threonine (T). 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.92	P;P;.;D
Vest4		0.75
MutPred		0.86		.;Loss of MoRF binding (P = 0.1051);.;.;
MVP		0.85
MPC		0.18
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.51
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-55378874;