Genetic Variant FRMPD2:p.Glu1276Gly (chr10-48163382-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001018071.4(FRMPD2):c.3827A>G(p.Glu1276Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FRMPD2
NM_001018071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

Publications

0 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41946262).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4 link	c.3827A>G	p.Glu1276Gly	missense_variant	Exon 28 of 29	ENST00000374201.8	NP_001018081.4	Q68DX3-1B4E1N9
FRMPD2	NM_001318191.1 link	c.3752A>G	p.Glu1251Gly	missense_variant	Exon 26 of 27		NP_001305120.1	Q68DX3
FRMPD2	NM_001042512.3 link	c.860A>G	p.Glu287Gly	missense_variant	Exon 5 of 6		NP_001035977.3	Q68DX3-4
FRMPD2	XM_017015744.2 link	c.683A>G	p.Glu228Gly	missense_variant	Exon 5 of 6		XP_016871233.1	Q68DX3-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMPD2	ENST00000374201.8 link	c.3827A>G	p.Glu1276Gly	missense_variant	Exon 28 of 29	1	NM_001018071.4	ENSP00000363317.3		Q68DX3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000344

AC:

AN:

872324

Hom.:

Cov.:

AF XY:

0.00000218

AC XY:

AN XY:

458072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21256

American (AMR)

AF:

0.00

AC:

AN:

43940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22294

East Asian (EAS)

AF:

0.00

AC:

AN:

36810

South Asian (SAS)

AF:

0.00

AC:

AN:

73884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2990

European-Non Finnish (NFE)

AF:

0.00000520

AC:

AN:

577306

Other (OTH)

AF:

0.00

AC:

AN:

40660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3827A>G (p.E1276G) alteration is located in exon 28 (coding exon 28) of the FRMPD2 gene. This alteration results from a A to G substitution at nucleotide position 3827, causing the glutamic acid (E) at amino acid position 1276 to be replaced by a glycine (G). 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

0.22

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.061

T;T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.76

T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.1

.;L;.

PhyloP100

4.2

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.1

.;D;D

REVEL

Benign

0.29

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

1.0

.;D;D

Vest4

0.30, 0.34

MVP

0.70

MPC

3.3

ClinPred

0.98

GERP RS

3.8

Varity_R

0.39

gMVP

0.30

Mutation Taster

=91/9

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over