11-61720854-C-T

Variant names:

• chr11-61720854-C-T
• rs2065275566
• NM_006133.3:c.271C>T

Variant summary

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

The NM_006133.3(DAGLA):​c.271C>T​(p.Arg91Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,100 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DAGLA NM_006133.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70

Genes affected

DAGLA (HGNC:1165): (diacylglycerol lipase alpha) This gene encodes a diacylglycerol lipase. The encoded enzyme is involved in the biosynthesis of the endocannabinoid 2-arachidonoyl-glycerol.[provided by RefSeq, Nov 2010]

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, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAGLA	NM_006133.3	c.271C>T	p.Arg91Cys	missense_variant	Exon 3 of 20	ENST00000257215.10	NP_006124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAGLA	ENST00000257215.10	c.271C>T	p.Arg91Cys	missense_variant	Exon 3 of 20	1	NM_006133.3	ENSP00000257215.5
DAGLA	ENST00000540717.1	n.271C>T		non_coding_transcript_exon_variant	Exon 3 of 20	5		ENSP00000440264.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461100 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726884

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.70		Gain of catalytic residue at P90 (P = 0.0137);
MVP		0.75
MPC		2.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.67
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2065275566; hg19: chr11-61488326; COSMIC: COSV57194037;