chr2-207946437-C-T

Position:

• chr2-207946437-C-T

Variant summary

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

The NM_001080475.3(PLEKHM3):​c.1622G>A​(p.Ser541Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: PLEKHM3 NM_001080475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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=0.11600238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM3	NM_001080475.3	c.1622G>A	p.Ser541Asn	missense_variant	4/8	ENST00000427836.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM3	ENST00000427836.8	c.1622G>A	p.Ser541Asn	missense_variant	4/8	5	NM_001080475.3	P1
PLEKHM3	ENST00000457206.1	c.1622G>A	p.Ser541Asn	missense_variant	4/8	1
PLEKHM3	ENST00000447645.5	c.878G>A	p.Ser293Asn	missense_variant	2/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Aug 23, 2021

The c.1622G>A (p.S541N) alteration is located in exon 4 (coding exon 3) of the PLEKHM3 gene. This alteration results from a G to A substitution at nucleotide position 1622, causing the serine (S) at amino acid position 541 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	Benign	0.099
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.0050	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.23
Sift	Benign	0.27	T;T
Sift4G	Benign	0.064	T;T
Polyphen		0.0010	B;B
Vest4		0.18
MutPred		0.42		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.49
MPC		1.0
ClinPred		0.20	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.33

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: chr2-208811161;