Genetic Variant MPP1:c.103-4G>A (chrX-154792289-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002436.4(MPP1):c.103-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,194,393 control chromosomes in the GnomAD database, including 21 homozygotes. There are 515 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0079 ( 7 hom., 270 hem., cov: 24)

Exomes 𝑓: 0.00089 ( 14 hom. 245 hem. )

Consequence

MPP1
NM_002436.4 splice_region, intron

Scores

Splicing: ADA: 0.000008560

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.224

Publications

1 publications found

Variant links:

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]

MPP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant X-154792289-C-T is Benign according to our data. Variant chrX-154792289-C-T is described in ClinVar as Benign. ClinVar VariationId is 714976.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00793 (893/112599) while in subpopulation AFR AF = 0.0276 (857/31005). AF 95% confidence interval is 0.0261. There are 7 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPP1	NM_002436.4 link	c.103-4G>A		splice_region_variant, intron_variant	Intron 1 of 11	ENST00000369534.8	NP_002427.1	Q00013-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPP1	ENST00000369534.8 link	c.103-4G>A		splice_region_variant, intron_variant	Intron 1 of 11	1	NM_002436.4	ENSP00000358547.3		Q00013-1

Frequencies

GnomAD3 genomes

AF:

0.00798

AC:

898

AN:

112548

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0279

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00225

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00722

GnomAD2 exomes

AF:

0.00237

AC:

407

AN:

171534

AF XY:

0.00188

show subpopulations

Gnomad AFR exome

AF:

0.0288

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000468

GnomAD4 exome

AF:

0.000887

AC:

960

AN:

1081794

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

245

AN XY:

349820

show subpopulations

African (AFR)

AF:

0.0306

AC:

801

AN:

26213

American (AMR)

AF:

0.00148

AC:

AN:

34486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18694

East Asian (EAS)

AF:

0.00

AC:

AN:

29885

South Asian (SAS)

AF:

0.0000384

AC:

AN:

52053

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39553

Middle Eastern (MID)

AF:

0.000490

AC:

AN:

4081

European-Non Finnish (NFE)

AF:

0.00000842

AC:

AN:

831394

Other (OTH)

AF:

0.00213

AC:

AN:

45435

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00793

AC:

893

AN:

112599

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

270

AN XY:

34765

show subpopulations

African (AFR)

AF:

0.0276

AC:

857

AN:

31005

American (AMR)

AF:

0.00225

AC:

AN:

10676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3588

South Asian (SAS)

AF:

0.00

AC:

AN:

2742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53251

Other (OTH)

AF:

0.00713

AC:

AN:

1543

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00557

Hom.:

Bravo

AF:

0.00923

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.21

(source)

DANN

Benign

0.31

PhyloP100

-0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000086

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over