8-6755078-T-C

Variant summary

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

The NM_018361.5(AGPAT5):c.773T>C(p.Ile258Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,444,024 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: 0.0000028 (0 hom.)
• Consequence: AGPAT5 NM_018361.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

Genes affected

AGPAT5 (HGNC:20886): (1-acylglycerol-3-phosphate O-acyltransferase 5) This gene encodes a member of the 1-acylglycerol-3-phosphate O-acyltransferase family. This integral membrane protein converts lysophosphatidic acid to phosphatidic acid, the second step in de novo phospholipid biosynthesis. A pseudogene of this gene is present on the Y chromosome. [provided by RefSeq, Aug 2014]

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, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGPAT5	NM_018361.5	c.773T>C	p.Ile258Thr	missense_variant	7/8	ENST00000285518.11
AGPAT5	XM_047421938.1	c.320T>C	p.Ile107Thr	missense_variant	6/7
AGPAT5	XM_047421939.1	c.320T>C	p.Ile107Thr	missense_variant	8/9
AGPAT5	XM_047421940.1	c.523T>C	p.Phe175Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPAT5	ENST00000285518.11	c.773T>C	p.Ile258Thr	missense_variant	7/8	1	NM_018361.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000425 AC: 1 AN: 235494 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444024 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 717822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000511

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: 9.03e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

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

Jul 27, 2022

The c.773T>C (p.I258T) alteration is located in exon 7 (coding exon 7) of the AGPAT5 gene. This alteration results from a T to C substitution at nucleotide position 773, causing the isoleucine (I) at amino acid position 258 to be replaced by a threonine (T). 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	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.28	B
Vest4		0.78
MutPred		0.77		Loss of stability (P = 0.0095);
MVP		0.85
MPC		0.036
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.28
gMVP		0.75

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: rs1449965581; hg19: chr8-6612599;