dbSNP rs376385156: FRMD1:p.Arg450Leu (chr6-168059182-C-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_024919.6(FRMD1):c.1349G>T(p.Arg450Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,966 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. 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. R450H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FRMD1
NM_024919.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.54

Publications

4 publications found

Variant links:

Genes affected

FRMD1 (HGNC:21240): (FERM domain containing 1) Predicted to be involved in positive regulation of hippo signaling. Predicted to be located in cytoskeleton. Predicted to be active in cytoplasmic side of apical plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

FRMD1 links:

Genome browser will be placed here

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=0.063688576).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024919.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRMD1	NM_024919.6	MANE Select	c.1349G>T	p.Arg450Leu	missense	Exon 10 of 11	NP_079195.3
FRMD1	NM_001394681.1		c.1154G>T	p.Arg385Leu	missense	Exon 9 of 10	NP_001381610.1	A0A2R8Y6M2
FRMD1	NM_001122841.3		c.1145G>T	p.Arg382Leu	missense	Exon 10 of 11	NP_001116313.1	Q8N878-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRMD1	ENST00000283309.11	TSL:1 MANE Select	c.1349G>T	p.Arg450Leu	missense	Exon 10 of 11	ENSP00000283309.6	Q8N878-1
FRMD1	ENST00000432403.5	TSL:1	n.1036G>T		non_coding_transcript_exon	Exon 8 of 9
FRMD1	ENST00000646385.1		c.1544G>T	p.Arg515Leu	missense	Exon 13 of 14	ENSP00000494166.1	A0A2R8Y4L9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000486

AC:

AN:

205700

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000324

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:

0.00000140

AC:

AN:

1432966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710642

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33228

American (AMR)

AF:

0.0000478

AC:

AN:

41816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25684

East Asian (EAS)

AF:

0.00

AC:

AN:

38738

South Asian (SAS)

AF:

0.00

AC:

AN:

82392

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5248

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101192

Other (OTH)

AF:

0.00

AC:

AN:

59386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.034

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0052

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.50

M_CAP

Benign

0.0029

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.29

PhyloP100

-2.5

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.2

REVEL

Benign

0.013

Sift

Benign

0.43

Sift4G

Benign

0.38

Polyphen

0.28

Vest4

0.13

MutPred

0.44

Loss of MoRF binding (P = 0.0115)

MVP

0.18

MPC

0.13

ClinPred

0.026

GERP RS

-4.4

Varity_R

0.036

gMVP

0.13

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over