Genetic Variant FRMPD2:p.Val1135Met (chr10-48171029-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001018071.4(FRMPD2):c.3403G>A(p.Val1135Met) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1135L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 23)

Exomes 𝑓: 0.000044 ( 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: 5.09

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4 link	c.3403G>A	p.Val1135Met	missense_variant	Exon 26 of 29	ENST00000374201.8	NP_001018081.4	Q68DX3-1B4E1N9
FRMPD2	NM_001318191.1 link	c.3328G>A	p.Val1110Met	missense_variant	Exon 24 of 27		NP_001305120.1	Q68DX3
FRMPD2	NM_001042512.3 link	c.436G>A	p.Val146Met	missense_variant	Exon 3 of 6		NP_001035977.3	Q68DX3-4
FRMPD2	XM_017015744.2 link	c.259G>A	p.Val87Met	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.3403G>A	p.Val1135Met	missense_variant	Exon 26 of 29	1	NM_001018071.4	ENSP00000363317.3		Q68DX3-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

145044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000274

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000348

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000458

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000801

AC:

AN:

37466

AF XY:

0.0000522

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:

0.0000836

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000439

AC:

AN:

705396

Hom.:

Cov.:

AF XY:

0.0000398

AC XY:

AN XY:

377310

show subpopulations

African (AFR)

AF:

0.000146

AC:

AN:

20500

American (AMR)

AF:

0.0000234

AC:

AN:

42706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20936

East Asian (EAS)

AF:

0.0000555

AC:

AN:

36066

South Asian (SAS)

AF:

0.0000855

AC:

AN:

70146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52140

Middle Eastern (MID)

AF:

0.000373

AC:

AN:

2680

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

424940

Other (OTH)

AF:

0.0000567

AC:

AN:

35282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000131

AC:

AN:

145160

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

70186

show subpopulations

African (AFR)

AF:

0.000273

AC:

AN:

40274

American (AMR)

AF:

0.000348

AC:

AN:

14384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3352

East Asian (EAS)

AF:

0.00

AC:

AN:

5008

South Asian (SAS)

AF:

0.00

AC:

AN:

4342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0000458

AC:

AN:

65442

Other (OTH)

AF:

0.00

AC:

AN:

1930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3403G>A (p.V1135M) alteration is located in exon 26 (coding exon 26) of the FRMPD2 gene. This alteration results from a G to A substitution at nucleotide position 3403, causing the valine (V) at amino acid position 1135 to be replaced by a methionine (M). 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

Pathogenic

0.62

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Benign

-0.49

MutationAssessor

Pathogenic

3.1

.;M;.

PhyloP100

5.1

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.7

.;D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

1.0

.;D;D

Vest4

0.68, 0.70

MVP

0.44

MPC

3.1

ClinPred

0.76

GERP RS

3.3

Varity_R

0.42

gMVP

0.38

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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10-48171029-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over