chr3-58274795-C-T

Variant names:

• chr3-58274795-C-T
• rs780341808
• NM_001320126.2:c.661C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001320126.2(ABHD6):​c.661C>T​(p.Arg221Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,654 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. R221S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (1 hom.)
• Consequence: ABHD6 NM_001320126.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320126.2. 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
	ABHD6	NM_001320126.2	MANE Select	c.661C>T	p.Arg221Cys	missense	Exon 7 of 10	NP_001307055.1	Q9BV23
	ABHD6	NM_020676.7		c.661C>T	p.Arg221Cys	missense	Exon 6 of 9	NP_065727.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD6	ENST00000478253.6	TSL:2 MANE Select	c.661C>T	p.Arg221Cys	missense	Exon 7 of 10	ENSP00000420315.1	Q9BV23
	ABHD6	ENST00000295962.8	TSL:1	c.661C>T	p.Arg221Cys	missense	Exon 6 of 9	ENSP00000295962.4	Q9BV23
	ABHD6	ENST00000972009.1		c.775C>T	p.Arg259Cys	missense	Exon 7 of 10	ENSP00000642068.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250722 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461654 Hom.: 1 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.000112 AC: 5 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.27
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.94
MPC		0.85
ClinPred		0.97	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.77
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780341808; hg19: chr3-58260522;