rs146907470

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001368397.1(FRMPD4):​c.2903C>T​(p.Ser968Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,210,032 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.000060 ( 0 hom. 23 hem. )

Consequence

FRMPD4
NM_001368397.1 missense

Scores

1
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.73
Variant links:
Genes affected
FRMPD4 (HGNC:29007): (FERM and PDZ domain containing 4) This gene encodes a multi-domain (WW, PDZ, FERM) containing protein. Through its interaction with other proteins (such as PSD-95), it functions as a positive regulator of dendritic spine morphogenesis and density, and is required for the maintenance of excitatory synaptic transmission. [provided by RefSeq, Jan 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07039344).
BP6
Variant X-12717729-C-T is Benign according to our data. Variant chrX-12717729-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211051.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High Hemizygotes in GnomAdExome4 at 23 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FRMPD4NM_001368397.1 linkc.2903C>T p.Ser968Leu missense_variant 16/17 ENST00000675598.1 NP_001355326.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FRMPD4ENST00000675598.1 linkc.2903C>T p.Ser968Leu missense_variant 16/17 NM_001368397.1 ENSP00000502607.1 A0A6Q8PH73

Frequencies

GnomAD3 genomes
AF:
0.0000622
AC:
7
AN:
112552
Hom.:
0
Cov.:
23
AF XY:
0.0000288
AC XY:
1
AN XY:
34706
show subpopulations
Gnomad AFR
AF:
0.0000646
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000279
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000751
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000601
AC:
11
AN:
183105
Hom.:
0
AF XY:
0.0000739
AC XY:
5
AN XY:
67625
show subpopulations
Gnomad AFR exome
AF:
0.0000762
Gnomad AMR exome
AF:
0.0000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000216
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000613
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.0000601
AC:
66
AN:
1097426
Hom.:
0
Cov.:
32
AF XY:
0.0000634
AC XY:
23
AN XY:
362790
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000265
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000654
Gnomad4 OTH exome
AF:
0.0000651
GnomAD4 genome
AF:
0.0000622
AC:
7
AN:
112606
Hom.:
0
Cov.:
23
AF XY:
0.0000288
AC XY:
1
AN XY:
34770
show subpopulations
Gnomad4 AFR
AF:
0.0000645
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000280
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000751
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 16, 2014- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 06, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.66
T
BayesDel_noAF
Benign
-0.89
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.022
T;T
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.85
T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.070
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.73
N;.
REVEL
Benign
0.066
Sift
Benign
0.093
T;.
Sift4G
Benign
0.20
T;T
Polyphen
0.0020
B;.
Vest4
0.17
MVP
0.12
MPC
0.11
ClinPred
0.042
T
GERP RS
5.7
Varity_R
0.14
gMVP
0.27

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.

Other links and lift over

dbSNP: rs146907470; hg19: chrX-12735848; API