4-128009110-T-A

Position:

• chr4-128009110-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001358451.3(ABHD18):​c.361T>A​(p.Tyr121Asn) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABHD18 NM_001358451.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

Genes affected

ABHD18 (HGNC:26111): (abhydrolase domain containing 18) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABHD18	NM_001358451.3	c.361T>A	p.Tyr121Asn	missense_variant	6/13	ENST00000645843.2	NP_001345380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABHD18	ENST00000645843.2	c.361T>A	p.Tyr121Asn	missense_variant	6/13		NM_001358451.3	ENSP00000496010.1
ABHD18	ENST00000444616.5	c.361T>A	p.Tyr121Asn	missense_variant	6/11	5		ENSP00000397229.1
ABHD18	ENST00000388795.10	n.*119T>A		non_coding_transcript_exon_variant	6/13	5		ENSP00000373447.6
ABHD18	ENST00000388795.10	n.*119T>A		3_prime_UTR_variant	6/13	5		ENSP00000373447.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422580 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 706286

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 17, 2024

The c.361T>A (p.Y121N) alteration is located in exon 6 (coding exon 5) of the ABHD18 gene. This alteration results from a T to A substitution at nucleotide position 361, causing the tyrosine (Y) at amino acid position 121 to be replaced by an asparagine (N). 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	0.90
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.52	T
PROVEAN	Pathogenic	-5.6	D;.;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.99	D;.;D;.
Vest4		0.90
MutPred		0.76		Gain of glycosylation at T126 (P = 0.0108);Gain of glycosylation at T126 (P = 0.0108);Gain of glycosylation at T126 (P = 0.0108);.;
MVP		0.69
MPC		0.71
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1754121442; hg19: chr4-128930265;