15-43874090-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_032892.5(FRMD5):​c.1508G>A​(p.Arg503His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

FRMD5
NM_032892.5 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
FRMD5 (HGNC:28214): (FERM domain containing 5) Enables integrin binding activity and protein kinase binding activity. Involved in negative regulation of cell motility; positive regulation of cell adhesion; and regulation of cell migration. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FRMD5NM_032892.5 linkc.1508G>A p.Arg503His missense_variant Exon 14 of 14 ENST00000417257.6 NP_116281.2 Q7Z6J6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FRMD5ENST00000417257.6 linkc.1508G>A p.Arg503His missense_variant Exon 14 of 14 1 NM_032892.5 ENSP00000403067.1 Q7Z6J6-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251336
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000930
AC:
136
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.0000935
AC XY:
68
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000108
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000650
Hom.:
0
Bravo
AF:
0.0000945
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 12, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1508G>A (p.R503H) alteration is located in exon 14 (coding exon 14) of the FRMD5 gene. This alteration results from a G to A substitution at nucleotide position 1508, causing the arginine (R) at amino acid position 503 to be replaced by a histidine (H). 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
Uncertain
0.34
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.24
T;T;T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.71
D;D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Uncertain
2.8
.;M;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-1.8
.;N;.
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0090
.;D;.
Sift4G
Uncertain
0.0030
D;T;.
Polyphen
1.0
.;D;.
Vest4
0.67
MVP
0.77
MPC
0.41
ClinPred
0.43
T
GERP RS
6.0
Varity_R
0.24
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs145058047; hg19: chr15-44166288; API