2-207976855-T-A

Position:

• chr2-207976855-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080475.3(PLEKHM3):​c.1342A>T​(p.Met448Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLEKHM3 NM_001080475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.48

Genes affected

PLEKHM3 (HGNC:34006): (pleckstrin homology domain containing M3) Predicted to enable metal ion binding activity. Predicted to be involved in myoblast differentiation. Predicted to be located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23947632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM3	NM_001080475.3	c.1342A>T	p.Met448Leu	missense_variant	3/8	ENST00000427836.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM3	ENST00000427836.8	c.1342A>T	p.Met448Leu	missense_variant	3/8	5	NM_001080475.3	P1
PLEKHM3	ENST00000457206.1	c.1342A>T	p.Met448Leu	missense_variant	3/8	1
PLEKHM3	ENST00000447645.5	c.598A>T	p.Met200Leu	missense_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

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: 8.99e-7

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

Jun 02, 2023

The c.1342A>T (p.M448L) alteration is located in exon 3 (coding exon 2) of the PLEKHM3 gene. This alteration results from a A to T substitution at nucleotide position 1342, causing the methionine (M) at amino acid position 448 to be replaced by a leucine (L). 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	Benign	0.24
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.14
Sift	Benign	0.43	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.32	B;P
Vest4		0.44
MutPred		0.56		Loss of catalytic residue at M448 (P = 0.0142);Loss of catalytic residue at M448 (P = 0.0142);
MVP		0.15
MPC		0.17
ClinPred		0.57	D
GERP RS		5.7
Varity_R		0.41
gMVP		0.39

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: rs1691329154; hg19: chr2-208841579;