NM_001018071.4:c.3214G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001018071.4(FRMPD2):c.3214G>C(p.Val1072Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,068,414 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 2 hom., cov: 20)

Exomes 𝑓: 0.00033 ( 91 hom. )

Failed GnomAD Quality Control

Consequence

FRMPD2
NM_001018071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056109816).

BS2

High Homozygotes in GnomAdExome4 at 91 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMPD2	NM_001018071.4 link	c.3214G>C	p.Val1072Leu	missense_variant	Exon 25 of 29	ENST00000374201.8	NP_001018081.4	Q68DX3-1B4E1N9
FRMPD2	NM_001318191.1 link	c.3139G>C	p.Val1047Leu	missense_variant	Exon 23 of 27		NP_001305120.1	Q68DX3
FRMPD2	NM_001042512.3 link	c.247G>C	p.Val83Leu	missense_variant	Exon 2 of 6		NP_001035977.3	Q68DX3-4
FRMPD2	XM_017015744.2 link	c.70G>C	p.Val24Leu	missense_variant	Exon 2 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.3214G>C	p.Val1072Leu	missense_variant	Exon 25 of 29	1	NM_001018071.4	ENSP00000363317.3		Q68DX3-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

125558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00102

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000291

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000173

AC:

AN:

219822

AF XY:

0.000160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000642

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000413

Gnomad NFE exome

AF:

0.000268

Gnomad OTH exome

AF:

0.000380

GnomAD4 exome

AF:

0.000327

AC:

349

AN:

1068414

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

174

AN XY:

538062

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30752

American (AMR)

AF:

0.0000999

AC:

AN:

40036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

36286

South Asian (SAS)

AF:

0.00

AC:

AN:

77008

European-Finnish (FIN)

AF:

0.000743

AC:

AN:

47100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3142

European-Non Finnish (NFE)

AF:

0.000385

AC:

296

AN:

768672

Other (OTH)

AF:

0.000282

AC:

AN:

46058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.597

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:

0.000191

AC:

AN:

125558

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

AN XY:

60710

show subpopulations

African (AFR)

AF:

0.0000267

AC:

AN:

37388

American (AMR)

AF:

0.00

AC:

AN:

12852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2776

East Asian (EAS)

AF:

0.00

AC:

AN:

4180

South Asian (SAS)

AF:

0.00

AC:

AN:

3900

European-Finnish (FIN)

AF:

0.00102

AC:

AN:

6856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000291

AC:

AN:

54982

Other (OTH)

AF:

0.00

AC:

AN:

1656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.645

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000378

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000699

AC:

ExAC

AF:

0.000134

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3214G>C (p.V1072L) alteration is located in exon 25 (coding exon 25) of the FRMPD2 gene. This alteration results from a G to C substitution at nucleotide position 3214, causing the valine (V) at amino acid position 1072 to be replaced by a leucine (L). 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

0.19

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.020

T;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;L;.

PhyloP100

3.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.5

.;N;N

REVEL

Benign

0.023

Sift

Benign

0.18

.;T;T

Sift4G

Benign

0.44

.;T;T

Polyphen

0.051, 0.0070

.;B;B

Vest4

0.079, 0.095

MutPred

0.16

Loss of methylation at K1077 (P = 0.137);Loss of methylation at K1077 (P = 0.137);.;

MVP

0.53

MPC

2.1

ClinPred

0.041

GERP RS

4.5

Varity_R

0.10

gMVP

0.13

Mutation Taster

=85/15

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.3214G>C

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