chr6-144421904-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007124.3(UTRN):​c.168G>A​(p.Met56Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000224 in 1,612,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. M56V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

UTRN
NM_007124.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.08
Variant links:
Genes affected
UTRN (HGNC:12635): (utrophin) This gene shares both structural and functional similarities with the dystrophin gene. It contains an actin-binding N-terminus, a triple coiled-coil repeat central region, and a C-terminus that consists of protein-protein interaction motifs which interact with dystroglycan protein components. The protein encoded by this gene is located at the neuromuscular synapse and myotendinous junctions, where it participates in post-synaptic membrane maintenance and acetylcholine receptor clustering. Mouse studies suggest that this gene may serve as a functional substitute for the dystrophin gene and therefore, may serve as a potential therapeutic alternative to muscular dystrophy which is caused by mutations in the dystrophin gene. Alternative splicing of the utrophin gene has been described; however, the full-length nature of these variants has not yet been determined. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.029669076).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
UTRNNM_007124.3 linkuse as main transcriptc.168G>A p.Met56Ile missense_variant 4/75 ENST00000367545.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UTRNENST00000367545.8 linkuse as main transcriptc.168G>A p.Met56Ile missense_variant 4/755 NM_007124.3 P1P46939-1
UTRNENST00000421035.2 linkuse as main transcriptc.183G>A p.Met61Ile missense_variant 3/62
UTRNENST00000628146.2 linkuse as main transcriptc.141G>A p.Met47Ile missense_variant 3/62

Frequencies

GnomAD3 genomes
AF:
0.000335
AC:
51
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.000323
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000296
AC:
74
AN:
250166
Hom.:
0
AF XY:
0.000318
AC XY:
43
AN XY:
135298
show subpopulations
Gnomad AFR exome
AF:
0.0000618
Gnomad AMR exome
AF:
0.000585
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000329
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000335
Gnomad OTH exome
AF:
0.00213
GnomAD4 exome
AF:
0.000214
AC:
312
AN:
1460524
Hom.:
1
Cov.:
30
AF XY:
0.000212
AC XY:
154
AN XY:
726564
show subpopulations
Gnomad4 AFR exome
AF:
0.000359
Gnomad4 AMR exome
AF:
0.000695
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000930
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000149
Gnomad4 OTH exome
AF:
0.000630
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152270
Hom.:
0
Cov.:
32
AF XY:
0.000403
AC XY:
30
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000323
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000346
Hom.:
0
Bravo
AF:
0.000465
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000305
AC:
37
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000548
EpiControl
AF:
0.000773

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 14, 2022The c.168G>A (p.M56I) alteration is located in exon 3 (coding exon 3) of the UTRN gene. This alteration results from a G to A substitution at nucleotide position 168, causing the methionine (M) at amino acid position 56 to be replaced by an isoleucine (I). 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
0.21
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.10
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.60
D;.;T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.060
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
D;T;T
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.030
T;T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
-0.40
N;.;.
MutationTaster
Benign
0.90
D
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-0.86
N;.;N
REVEL
Uncertain
0.30
Sift
Benign
0.087
T;.;D
Sift4G
Benign
0.20
.;T;T
Polyphen
0.0010
B;.;.
Vest4
0.50
MutPred
0.52
Loss of disorder (P = 0.0887);.;.;
MVP
0.59
MPC
0.15
ClinPred
0.049
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.64

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: rs144223166; hg19: chr6-144743040; COSMIC: COSV100840862; API