Genetic Variant NM_001018071.4:c.3347C>A (chr10-48171085-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001018071.4(FRMPD2):c.3347C>A(p.Pro1116Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P1116L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FRMPD2
NM_001018071.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.78

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4 link	c.3347C>A	p.Pro1116Gln	missense_variant	Exon 26 of 29	ENST00000374201.8	NP_001018081.4	Q68DX3-1B4E1N9
FRMPD2	NM_001318191.1 link	c.3272C>A	p.Pro1091Gln	missense_variant	Exon 24 of 27		NP_001305120.1	Q68DX3
FRMPD2	NM_001042512.3 link	c.380C>A	p.Pro127Gln	missense_variant	Exon 3 of 6		NP_001035977.3	Q68DX3-4
FRMPD2	XM_017015744.2 link	c.203C>A	p.Pro68Gln	missense_variant	Exon 3 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.3347C>A	p.Pro1116Gln	missense_variant	Exon 26 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:

0.00000146

AC:

AN:

685862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

365938

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19976

American (AMR)

AF:

0.00

AC:

AN:

42192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20750

East Asian (EAS)

AF:

0.00

AC:

AN:

35724

South Asian (SAS)

AF:

0.00

AC:

AN:

69680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2608

European-Non Finnish (NFE)

AF:

0.00000245

AC:

AN:

408420

Other (OTH)

AF:

0.00

AC:

AN:

34556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.6

.;M;.

PhyloP100

4.8

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.6

.;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0010

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.43, 0.45

MutPred

0.62

Gain of ubiquitination at K1112 (P = 0.0635);Gain of ubiquitination at K1112 (P = 0.0635);.;

MVP

0.51

MPC

3.0

ClinPred

0.98

GERP RS

2.4

Varity_R

0.42

gMVP

0.28

Mutation Taster

=86/14

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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NM_001018071.4:c.3347C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over