dbSNP rs762841876: FRMD3:p.Ile408Phe (chr9-83248490-T-A) – 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_174938.6(FRMD3):c.1222A>T(p.Ile408Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I408V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FRMD3
NM_174938.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.751

Publications

0 publications found

Variant links:

Genes affected

FRMD3 (HGNC:24125): (FERM domain containing 3) The protein encoded by this gene is a single pass membrane protein primarily found in ovaries. A similar protein in erythrocytes helps determine the shape of red blood cells, but the function of the encoded protein has not been determined. There is some evidence that this is a tumor suppressor gene, and there is also evidence linking defects in this gene to susceptibility to diabetic nephropathy in type 1 diabetes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

FRMD3 links:

FRMD3-AS1 (HGNC:55790): (FRMD3 antisense RNA 1)

FRMD3-AS1 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=0.047219038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD3	NM_174938.6 link	c.1222A>T	p.Ile408Phe	missense_variant	Exon 14 of 14	ENST00000304195.8	NP_777598.3	A2A2Y4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD3	ENST00000304195.8 link	c.1222A>T	p.Ile408Phe	missense_variant	Exon 14 of 14	1	NM_174938.6	ENSP00000303508.3		A2A2Y4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.00

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111508

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

0.069

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

9.6

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0046

.;.;.;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.047

T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.90

.;.;L;L;.

PhyloP100

0.75

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

N;N;N;N;.

REVEL

Benign

0.13

Sift

Benign

0.28

T;T;T;T;.

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

0.46

P;.;B;B;.

Vest4

0.23

MutPred

0.11

.;.;Loss of phosphorylation at S409 (P = 0.2465);Loss of phosphorylation at S409 (P = 0.2465);.;

MVP

0.50

MPC

0.28

ClinPred

0.049

GERP RS

-0.92

Varity_R

0.080

gMVP

0.20

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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