19-46746405-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_013403.3(STRN4):​c.26C>A​(p.Ala9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,052,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

STRN4
NM_013403.3 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Publications

1 publications found
Variant links:
Genes affected
STRN4 (HGNC:15721): (striatin 4) Enables armadillo repeat domain binding activity and protein phosphatase 2A binding activity. Part of FAR/SIN/STRIPAK complex. [provided by Alliance of Genome Resources, Apr 2022]
FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]
FKRP Gene-Disease associations (from GenCC):
  • autosomal recessive limb-girdle muscular dystrophy type 2I
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
  • muscular dystrophy-dystroglycanopathy type B5
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
  • myopathy caused by variation in FKRP
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • congenital muscular dystrophy with cerebellar involvement
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy with intellectual disability
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy without intellectual disability
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • muscle-eye-brain disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • muscular dystrophy-dystroglycanopathy, type A
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.120658636).
BS2
High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STRN4NM_013403.3 linkc.26C>A p.Ala9Glu missense_variant Exon 1 of 18 ENST00000263280.11 NP_037535.2 Q9NRL3-1
FKRPNM_024301.5 linkc.-253+315G>T intron_variant Intron 1 of 3 ENST00000318584.10 NP_077277.1 Q9H9S5A0A024R0R7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STRN4ENST00000263280.11 linkc.26C>A p.Ala9Glu missense_variant Exon 1 of 18 1 NM_013403.3 ENSP00000263280.4 Q9NRL3-1
FKRPENST00000318584.10 linkc.-253+315G>T intron_variant Intron 1 of 3 1 NM_024301.5 ENSP00000326570.4 Q9H9S5

Frequencies

GnomAD3 genomes
AF:
0.0000136
AC:
2
AN:
146892
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000303
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000453
AC:
41
AN:
905072
Hom.:
0
Cov.:
33
AF XY:
0.0000354
AC XY:
15
AN XY:
423624
show subpopulations
African (AFR)
AF:
0.000115
AC:
2
AN:
17380
American (AMR)
AF:
0.00
AC:
0
AN:
3280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
7276
East Asian (EAS)
AF:
0.00
AC:
0
AN:
7970
South Asian (SAS)
AF:
0.00
AC:
0
AN:
17858
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
7454
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
1994
European-Non Finnish (NFE)
AF:
0.0000457
AC:
37
AN:
810210
Other (OTH)
AF:
0.0000632
AC:
2
AN:
31650
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000136
AC:
2
AN:
147000
Hom.:
0
Cov.:
30
AF XY:
0.0000279
AC XY:
2
AN XY:
71668
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
40728
American (AMR)
AF:
0.00
AC:
0
AN:
14890
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3384
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5024
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4804
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8918
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.0000303
AC:
2
AN:
66006
Other (OTH)
AF:
0.00
AC:
0
AN:
2046
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.650
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 17, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.26C>A (p.A9E) alteration is located in exon 1 (coding exon 1) of the STRN4 gene. This alteration results from a C to A substitution at nucleotide position 26, causing the alanine (A) at amino acid position 9 to be replaced by a glutamic acid (E). 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
0.19
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.032
T;.
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.77
FATHMM_MKL
Benign
0.024
N
LIST_S2
Benign
0.48
T;T
M_CAP
Pathogenic
0.37
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.34
N;N
PhyloP100
2.6
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.20
N;N
REVEL
Benign
0.076
Sift
Uncertain
0.0070
D;D
Sift4G
Benign
1.0
T;T
Polyphen
0.10
B;.
Vest4
0.17
MutPred
0.34
Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP
0.082
MPC
0.49
ClinPred
0.27
T
GERP RS
2.7
PromoterAI
-0.023
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.1
Varity_R
0.20
gMVP
0.57
Mutation Taster
=91/9
polymorphism

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

Other links and lift over

dbSNP: rs1179519325; hg19: chr19-47249662; API