10-28089817-A-C

Variant names:

• chr10-28089817-A-C
• rs746532119
• NM_001318170.2:c.977T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001318170.2(MPP7):​c.977T>G​(p.Leu326Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000919 in 1,414,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: MPP7 NM_001318170.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.94
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318170.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPP7	NM_001318170.2	MANE Select	c.977T>G	p.Leu326Arg	missense	Exon 12 of 17	NP_001305099.1	Q5T2T1-1
	MPP7	NM_173496.5		c.977T>G	p.Leu326Arg	missense	Exon 14 of 19	NP_775767.2	Q5T2T1-1
	MPP7	NR_134517.2		n.1312T>G		non_coding_transcript_exon	Exon 12 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPP7	ENST00000683449.1	MANE Select	c.977T>G	p.Leu326Arg	missense	Exon 12 of 17	ENSP00000507917.1	Q5T2T1-1
	MPP7	ENST00000375719.7	TSL:1	c.977T>G	p.Leu326Arg	missense	Exon 14 of 19	ENSP00000364871.3	Q5T2T1-1
	MPP7	ENST00000496637.6	TSL:1	n.977T>G		non_coding_transcript_exon	Exon 11 of 16	ENSP00000473899.1	S4R337

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000205 AC: 5 AN: 243392 AF XY: 0.0000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000919 AC: 13 AN: 1414740 Hom.: 0 Cov.: 26 AF XY: 0.00000851 AC XY: 6 AN XY: 705208

African (AFR) AF: 0.00 AC: 0 AN: 32436

American (AMR) AF: 0.0000229 AC: 1 AN: 43628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25614

East Asian (EAS) AF: 0.00 AC: 0 AN: 39340

South Asian (SAS) AF: 0.0000981 AC: 8 AN: 81512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1075090

Other (OTH) AF: 0.00 AC: 0 AN: 58696

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.53
Sift	Benign	0.052	T
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.32		Loss of stability (P = 0.0262)
MVP		0.95
MPC		0.83
ClinPred		0.93	D
GERP RS		5.8
Varity_R		0.46
gMVP		0.65
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs746532119; hg19: chr10-28378746; COSMIC: COSV61737932;