Genetic Variant NM_001018071.4:c.3869T>C (chr10-48163340-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001018071.4(FRMPD2):c.3869T>C(p.Met1290Thr) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1290R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FRMPD2
NM_001018071.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.217

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058684528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4 link	c.3869T>C	p.Met1290Thr	missense_variant	Exon 28 of 29	ENST00000374201.8	NP_001018081.4	Q68DX3-1B4E1N9
FRMPD2	NM_001318191.1 link	c.3794T>C	p.Met1265Thr	missense_variant	Exon 26 of 27		NP_001305120.1	Q68DX3
FRMPD2	NM_001042512.3 link	c.902T>C	p.Met301Thr	missense_variant	Exon 5 of 6		NP_001035977.3	Q68DX3-4
FRMPD2	XM_017015744.2 link	c.725T>C	p.Met242Thr	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.3869T>C	p.Met1290Thr	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:

0.00000101

AC:

AN:

994172

Hom.:

Cov.:

AF XY:

0.00000194

AC XY:

AN XY:

514434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23516

American (AMR)

AF:

0.00

AC:

AN:

44106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23000

East Asian (EAS)

AF:

0.00

AC:

AN:

37326

South Asian (SAS)

AF:

0.00

AC:

AN:

76390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3214

European-Non Finnish (NFE)

AF:

0.00000145

AC:

AN:

688750

Other (OTH)

AF:

0.00

AC:

AN:

44668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Benign

0.072

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0066

T;T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.47

T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;.

PhyloP100

0.22

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.050

.;N;N

REVEL

Benign

0.044

Sift

Benign

0.077

.;T;T

Sift4G

Benign

0.18

.;T;T

Polyphen

0.0010

.;B;B

Vest4

0.24, 0.23

MVP

0.23

MPC

1.9

ClinPred

0.094

GERP RS

0.55

Varity_R

0.085

gMVP

0.22

Mutation Taster

=97/3

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

Computational scores

Splicing

Publications

Other links and lift over