Genetic Variant FRMPD2:p.Cys1009Tyr (chr10-48174919-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001018071.4(FRMPD2):c.3026G>A(p.Cys1009Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000083 ( 0 hom., cov: 14)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

FRMPD2
NM_001018071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.64

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14411518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4 link	c.3026G>A	p.Cys1009Tyr	missense_variant	Exon 24 of 29	ENST00000374201.8	NP_001018081.4	Q68DX3-1B4E1N9
FRMPD2	NM_001318191.1 link	c.2951G>A	p.Cys984Tyr	missense_variant	Exon 22 of 27		NP_001305120.1	Q68DX3
FRMPD2	NM_001042512.3 link	c.59G>A	p.Cys20Tyr	missense_variant	Exon 1 of 6		NP_001035977.3	Q68DX3-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMPD2	ENST00000374201.8 link	c.3026G>A	p.Cys1009Tyr	missense_variant	Exon 24 of 29	1	NM_001018071.4	ENSP00000363317.3		Q68DX3-1

Frequencies

GnomAD3 genomes

AF:

0.00000832

AC:

AN:

120262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000338

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000503

AC:

AN:

59640

AF XY:

0.0000668

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000849

AC:

AN:

553426

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

295994

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17240

American (AMR)

AF:

0.00

AC:

AN:

29886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18988

East Asian (EAS)

AF:

0.00

AC:

AN:

32520

South Asian (SAS)

AF:

0.000804

AC:

AN:

58476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

315796

Other (OTH)

AF:

0.00

AC:

AN:

29598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000831

AC:

AN:

120346

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

56764

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31208

American (AMR)

AF:

0.00

AC:

AN:

11256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3076

East Asian (EAS)

AF:

0.00

AC:

AN:

4210

South Asian (SAS)

AF:

0.000339

AC:

AN:

2954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58072

Other (OTH)

AF:

0.00

AC:

AN:

1516

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000323

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3026G>A (p.C1009Y) alteration is located in exon 24 (coding exon 24) of the FRMPD2 gene. This alteration results from a G to A substitution at nucleotide position 3026, causing the cysteine (C) at amino acid position 1009 to be replaced by a tyrosine (Y). 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

0.14

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.074

T;T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.24

T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

.;N;.

PhyloP100

2.6

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.6

.;D;D

REVEL

Benign

0.12

Sift

Benign

0.066

.;T;T

Sift4G

Benign

0.16

.;T;T

Polyphen

1.0, 1.0

.;D;D

Vest4

0.18, 0.20

MutPred

0.41

Gain of methylation at K1014 (P = 0.0972);Gain of methylation at K1014 (P = 0.0972);.;

MVP

0.30

MPC

2.6

ClinPred

0.62

GERP RS

2.0

Varity_R

0.25

gMVP

0.21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

10-48174919-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over