3-58271014-C-A

Variant names:

• chr3-58271014-C-A
• NM_001320126.2:c.473C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001320126.2(ABHD6):​c.473C>A​(p.Ala158Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABHD6 NM_001320126.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

ABHD6 (HGNC:21398): (abhydrolase domain containing 6, acylglycerol lipase) Enables acylglycerol lipase activity. Involved in acylglycerol catabolic process. Predicted to be located in late endosome membrane and lysosomal membrane. Predicted to be integral component of membrane. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in GABA-ergic synapse; glutamatergic synapse; and mitochondrion. Predicted to be integral component of postsynaptic membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABHD6	NM_001320126.2	c.473C>A	p.Ala158Asp	missense_variant	Exon 6 of 10	ENST00000478253.6	NP_001307055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABHD6	ENST00000478253.6	c.473C>A	p.Ala158Asp	missense_variant	Exon 6 of 10	2	NM_001320126.2	ENSP00000420315.1
ABHD6	ENST00000295962.8	c.473C>A	p.Ala158Asp	missense_variant	Exon 5 of 9	1		ENSP00000295962.4
ABHD6	ENST00000463756.5	c.473C>A	p.Ala158Asp	missense_variant	Exon 6 of 7	3		ENSP00000420408.1
ABHD6	ENST00000485900.1	c.473C>A	p.Ala158Asp	missense_variant	Exon 5 of 5	5		ENSP00000418934.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460454 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.473C>A (p.A158D) alteration is located in exon 5 (coding exon 4) of the ABHD6 gene. This alteration results from a C to A substitution at nucleotide position 473, causing the alanine (A) at amino acid position 158 to be replaced by an aspartic acid (D). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;T;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H;H;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.98
MutPred		0.75		Gain of glycosylation at Y157 (P = 0.0188);Gain of glycosylation at Y157 (P = 0.0188);Gain of glycosylation at Y157 (P = 0.0188);Gain of glycosylation at Y157 (P = 0.0188);
MVP		0.99
MPC		0.97
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.90
gMVP		0.97

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: chr3-58256741;