Genetic Variant FRMPD2:p.Ser963Arg (chr10-48178053-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001018071.4(FRMPD2):c.2889T>A(p.Ser963Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000021 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

FRMPD2
NM_001018071.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.95

Publications

1 publications found

Variant links:

Genes affected

FRMPD2 (HGNC:28572): (FERM and PDZ domain containing 2) This gene encodes a peripheral membrane protein and is located in a region of chromosome 10q that contains a segmental duplication. This copy of the gene is full-length and is in the telomeric duplicated region. Two other more centromerically proximal copies of the gene are partial and may represent pseudogenes. This full-length gene appears to function in the establishment and maintenance of cell polarization. The protein is recruited to cell-cell junctions in an E-cadherin-dependent manner, and is selectively localized at the basolateral membrane in polarized epithelial cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2009]

FRMPD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FRMPD2	NM_001018071.4 link	c.2889T>A	p.Ser963Arg	missense_variant	Exon 22 of 29	ENST00000374201.8	NP_001018081.4
FRMPD2	NM_001318191.1 link	c.2814T>A	p.Ser938Arg	missense_variant	Exon 20 of 27		NP_001305120.1
FRMPD2	XM_047424652.1 link	c.2886T>A	p.Ser962Arg	missense_variant	Exon 22 of 22		XP_047280608.1
FRMPD2	XM_047424653.1 link	c.2796T>A	p.Ser932Arg	missense_variant	Exon 20 of 20		XP_047280609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMPD2	ENST00000374201.8 link	c.2889T>A	p.Ser963Arg	missense_variant	Exon 22 of 29	1	NM_001018071.4	ENSP00000363317.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000208

AC:

AN:

1444800

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719968

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33048

American (AMR)

AF:

0.0000448

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26032

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

85764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1098538

Other (OTH)

AF:

0.00

AC:

AN:

59696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.0046

BayesDel_noAF

Benign

-0.24

CADD

Benign

1.4

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.9

.;L;.

PhyloP100

-2.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.3

.;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.0030

.;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.88, 0.87

MutPred

0.82

Gain of methylation at S963 (P = 0.0558);Gain of methylation at S963 (P = 0.0558);.;

MVP

0.22

MPC

3.2

ClinPred

0.99

GERP RS

-2.1

Varity_R

0.77

gMVP

0.54

Mutation Taster

=59/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over