Genetic Variant FRMD1:p.Gln456Lys (chr6-168059165-G-T) – 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.1366C>A(p.Gln456Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,586,756 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. Q456R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

FRMD1
NM_024919.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.09

Publications

19 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:

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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=0.022548527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRMD1	NM_024919.6 link	c.1366C>A	p.Gln456Lys	missense_variant	Exon 10 of 11	ENST00000283309.11	NP_079195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRMD1	ENST00000283309.11 link	c.1366C>A	p.Gln456Lys	missense_variant	Exon 10 of 11	1	NM_024919.6	ENSP00000283309.6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000571

AC:

AN:

210202

AF XY:

0.0000615

show subpopulations

Gnomad AFR exome

AF:

0.000150

Gnomad AMR exome

AF:

0.000161

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000212

Gnomad OTH exome

AF:

0.000375

GnomAD4 exome

AF:

0.0000181

AC:

AN:

1434702

Hom.:

Cov.:

AF XY:

0.0000211

AC XY:

AN XY:

711742

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33262

American (AMR)

AF:

0.000167

AC:

AN:

41898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25744

East Asian (EAS)

AF:

0.00

AC:

AN:

38840

South Asian (SAS)

AF:

0.0000363

AC:

AN:

82632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45256

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5266

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

1102330

Other (OTH)

AF:

0.0000336

AC:

AN:

59474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41408

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000124

Hom.:

6234

ExAC

AF:

0.0000506

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.0040

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.0

.;.;T;.;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.16

T;T;T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.023

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.;N;.;.

PhyloP100

-1.1

PrimateAI

Benign

0.26

PROVEAN

Benign

0.0

.;.;N;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;T;T;.

Sift4G

Pathogenic

0.0

.;.;T;T;.

Vest4

0.0

ClinPred

0.0050

GERP RS

0.24

Varity_R

0.039

gMVP

0.11

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over