chr17-43823944-A-G

Position:

• chr17-43823944-A-G

Variant summary

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

The NM_001932.6(MPP3):​c.671T>C​(p.Leu224Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 6.9e-7 (0 hom.)
• Consequence: MPP3 NM_001932.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

MPP3 (HGNC:7221): (MAGUK p55 scaffold protein 3) This gene product is a member of a family of membrane-associated proteins termed MAGUKs (membrane-associated guanylate kinase homologs). MAGUKs interact with the cytoskeleton and regulate cell proliferation, signaling pathways, and intracellular junctions. This protein contains a conserved sequence, called the SH3 (src homology 3) motif, found in several other proteins that associate with the cytoskeleton and are suspected to play important roles in signal transduction. Alternatively spliced transcript variants have been identified. One transcript variant is experimentally supported, but it doesn't encode a protein. [provided by RefSeq, Jul 2008]

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=0.15141374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPP3	NM_001932.6	c.671T>C	p.Leu224Ser	missense_variant	10/20	ENST00000398389.9	NP_001923.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPP3	ENST00000398389.9	c.671T>C	p.Leu224Ser	missense_variant	10/20	1	NM_001932.6	ENSP00000381425	P1
MPP3	ENST00000398393.5	c.746T>C	p.Leu249Ser	missense_variant	8/18	1		ENSP00000381430
MPP3	ENST00000589375.5	n.986T>C		non_coding_transcript_exon_variant	11/13	1
MPP3	ENST00000496503.5	c.671T>C	p.Leu224Ser	missense_variant, NMD_transcript_variant	10/19	1		ENSP00000465486

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458842 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725756

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

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: 0.00

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

Sep 21, 2021

The c.671T>C (p.L224S) alteration is located in exon 10 (coding exon 8) of the MPP3 gene. This alteration results from a T to C substitution at nucleotide position 671, causing the leucine (L) at amino acid position 224 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.022	.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.30	.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.095
Sift	Benign	0.40	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0030	B;B
Vest4		0.26
MutPred		0.46		Loss of stability (P = 0.0017);.;
MVP		0.43
MPC		0.65
ClinPred		0.57	D
GERP RS		4.7
Varity_R		0.065
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2045578642; hg19: chr17-41901312;