19-1879927-C-T

Variant names:

• chr19-1879927-C-T
• rs1441854901
• NM_001130111.2:c.521G>A

Variant summary

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

The NM_001130111.2(ABHD17A):​c.521G>A​(p.Arg174His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,432 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: 6.9e-7 (0 hom.)
• Consequence: ABHD17A NM_001130111.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72

Genes affected

ABHD17A (HGNC:28756): (abhydrolase domain containing 17A, depalmitoylase) Enables palmitoyl-(protein) hydrolase activity. Involved in protein depalmitoylation and protein localization to membrane. Located in endosome membrane; nuclear speck; and plasma 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, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABHD17A	NM_001130111.2	c.521G>A	p.Arg174His	missense_variant	Exon 3 of 5	ENST00000292577.12	NP_001123583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABHD17A	ENST00000292577.12	c.521G>A	p.Arg174His	missense_variant	Exon 3 of 5	1	NM_001130111.2	ENSP00000292577.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183604 Hom.: 0 AF XY: 0.00000991 AC XY: 1 AN XY: 100862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000380

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454432 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723418

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.674G>A (p.R225H) alteration is located in exon 4 (coding exon 3) of the ABHD17A gene. This alteration results from a G to A substitution at nucleotide position 674, causing the arginine (R) at amino acid position 225 to be replaced by a histidine (H). 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	0.61
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.017	D;D;.
Sift4G	Benign	0.11	T;T;D
Polyphen		1.0	D;P;.
Vest4		0.90
MutPred		0.46		Loss of catalytic residue at R174 (P = 0.0951);.;.;
MVP		0.74
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.59
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs1441854901; hg19: chr19-1879926;