X-154785108-T-G

Variant names:

• chrX-154785108-T-G
• NM_002436.4:c.727A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002436.4(MPP1):​c.727A>C​(p.Ser243Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: MPP1 NM_002436.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

Genes affected

MPP1 (HGNC:7219): (MAGUK p55 scaffold protein 1) This gene encodes the prototype of the membrane-associated guanylate kinase (MAGUK) family proteins. MAGUKs interact with the cytoskeleton and regulate cell proliferation, signaling pathways, and intercellular junctions. The encoded protein is an extensively palmitoylated membrane phosphoprotein containing a PDZ domain, a Src homology 3 (SH3) motif, and a guanylate kinase domain. This gene product interacts with various cytoskeletal proteins and cell junctional proteins in different tissue and cell types, and may be involved in the regulation of cell shape, hair cell development, neural patterning of the retina, and apico-basal polarity and tumor suppression pathways in non-erythroid cells. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity EM55_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPP1	NM_002436.4	c.727A>C	p.Ser243Arg	missense_variant	Exon 7 of 12	ENST00000369534.8	NP_002427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPP1	ENST00000369534.8	c.727A>C	p.Ser243Arg	missense_variant	Exon 7 of 12	1	NM_002436.4	ENSP00000358547.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.727A>C (p.S243R) alteration is located in exon 7 (coding exon 7) of the MPP1 gene. This alteration results from a A to C substitution at nucleotide position 727, causing the serine (S) at amino acid position 243 to be replaced by an arginine (R). 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	0.95
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.086	T;T;D;T;D;D
Sift4G	Benign	0.23	T;T;T;.;.;.
Polyphen		0.98	D;.;.;D;.;.
Vest4		0.40
MutPred		0.27		Gain of MoRF binding (P = 0.0136);.;.;.;.;.;
MVP		0.90
MPC		1.3
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.66
gMVP		0.82

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: chrX-154013383;