2-207976789-T-C

Position:

• chr2-207976789-T-C

Variant summary

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

The NM_001080475.3(PLEKHM3):​c.1408A>G​(p.Arg470Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PLEKHM3 NM_001080475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.955

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM3	NM_001080475.3	c.1408A>G	p.Arg470Gly	missense_variant	3/8	ENST00000427836.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM3	ENST00000427836.8	c.1408A>G	p.Arg470Gly	missense_variant	3/8	5	NM_001080475.3	P1
PLEKHM3	ENST00000457206.1	c.1408A>G	p.Arg470Gly	missense_variant	3/8	1
PLEKHM3	ENST00000447645.5	c.664A>G	p.Arg222Gly	missense_variant	1/7	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 20, 2024

The c.1408A>G (p.R470G) alteration is located in exon 3 (coding exon 2) of the PLEKHM3 gene. This alteration results from a A to G substitution at nucleotide position 1408, causing the arginine (R) at amino acid position 470 to be replaced by a glycine (G). 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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0057	T;.
Eigen	Benign	0.021
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.73	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.19	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.40		Loss of MoRF binding (P = 0.008);Loss of MoRF binding (P = 0.008);
MVP		0.52
MPC		0.72
ClinPred		0.49	T
GERP RS		-0.46
Varity_R		0.30
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-208841513;