Variant 3-69181696-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015123.3(FRMD4B):c.2054C>G(p.Ser685Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000734 in 1,610,782 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 1 hom. )

Consequence

FRMD4B
NM_015123.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.73

Variant links:

Genes affected

FRMD4B (HGNC:24886): (FERM domain containing 4B) This gene encodes a GRP1-binding protein which contains a FERM protein interaction domain as well as two coiled coil domains. This protein may play a role as a scaffolding protein. [provided by RefSeq, Mar 2014]

FRMD4B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027339071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRMD4B	NM_015123.3 linkuse as main transcript	c.2054C>G	p.Ser685Cys	missense_variant	21/23	ENST00000398540.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRMD4B	ENST00000398540.8 linkuse as main transcript	c.2054C>G	p.Ser685Cys	missense_variant	21/23	1	NM_015123.3	P1	Q9Y2L6-1
FRMD4B	ENST00000478263.5 linkuse as main transcript	c.1010C>G	p.Ser337Cys	missense_variant	11/13	1

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000567

AC:

138

AN:

243484

Hom.:

AF XY:

0.000544

AC XY:

AN XY:

132248

show subpopulations

Gnomad AFR exome

AF:

0.000397

Gnomad AMR exome

AF:

0.000681

Gnomad ASJ exome

AF:

0.000708

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000878

Gnomad OTH exome

AF:

0.000843

GnomAD4 exome

AF:

0.000753

AC:

1098

AN:

1458506

Hom.:

Cov.:

AF XY:

0.000750

AC XY:

544

AN XY:

725372

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.000723

Gnomad4 ASJ exome

AF:

0.000422

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000905

Gnomad4 OTH exome

AF:

0.000614

GnomAD4 genome

AF:

0.000552

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000907

Hom.:

Bravo

AF:

0.000601

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000254

AC:

ESP6500EA

AF:

0.00120

AC:

ExAC

AF:

0.000538

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.2054C>G (p.S685C) alteration is located in exon 21 (coding exon 21) of the FRMD4B gene. This alteration results from a C to G substitution at nucleotide position 2054, causing the serine (S) at amino acid position 685 to be replaced by a cysteine (C). 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

0.071

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.0091

T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.027

T;T

MetaSVM

Uncertain

0.040

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.024

D;D

Sift4G

Uncertain

0.053

T;T

Polyphen

0.69

P;.

Vest4

0.31

MVP

0.45

MPC

0.15

ClinPred

0.041

GERP RS

6.0

Varity_R

0.073

gMVP

0.15

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over