10-28089830-T-G

Variant summary

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

The NM_001318170.2(MPP7):c.964A>C(p.Lys322Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000755 in 1,323,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K322R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: MPP7 NM_001318170.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

Genes affected

MPP7 (HGNC:26542): (MAGUK p55 scaffold protein 7) The protein encoded by this gene is a member of the p55 Stardust family of membrane-associated guanylate kinase (MAGUK) proteins, which function in the establishment of epithelial cell polarity. This family member forms a complex with the polarity protein DLG1 (discs, large homolog 1) and facilitates epithelial cell polarity and tight junction formation. Polymorphisms in this gene are associated with variations in site-specific bone mineral density (BMD). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

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=0.22563386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPP7	NM_001318170.2	c.964A>C	p.Lys322Gln	missense_variant	12/17	ENST00000683449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPP7	ENST00000683449.1	c.964A>C	p.Lys322Gln	missense_variant	12/17		NM_001318170.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1323666 Hom.: 0 Cov.: 21 AF XY: 0.00000151 AC XY: 1 AN XY: 663438

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: 9.99e-7

Gnomad4 OTH exome AF: 0.00

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

Jun 23, 2023

The c.964A>C (p.K322Q) alteration is located in exon 14 (coding exon 11) of the MPP7 gene. This alteration results from a A to C substitution at nucleotide position 964, causing the lysine (K) at amino acid position 322 to be replaced by a glutamine (Q). 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	0.34
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.045	T;T;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;.;.;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.34	N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.66	N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;T
Polyphen		0.010	B;B;B;.
Vest4		0.24
MutPred		0.33		Loss of methylation at K322 (P = 0.0121);Loss of methylation at K322 (P = 0.0121);Loss of methylation at K322 (P = 0.0121);.;
MVP		0.76
MPC		0.19
ClinPred		0.91	D
GERP RS		4.6
Varity_R		0.31
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr10-28378759;