6-144421904-G-A

Position:

• chr6-144421904-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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 (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: UTRN NM_007124.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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]

ACMG classification

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	Protein	UniProt
UTRN	NM_007124.3	c.168G>A	p.Met56Ile	missense_variant	4/75	ENST00000367545.8	NP_009055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UTRN	ENST00000367545.8	c.168G>A	p.Met56Ile	missense_variant	4/75	5	NM_007124.3	ENSP00000356515.3
UTRN	ENST00000421035.2	c.183G>A	p.Met61Ile	missense_variant	3/6	2		ENSP00000396276.2
UTRN	ENST00000628146.2	c.141G>A	p.Met47Ile	missense_variant	3/6	2		ENSP00000487153.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152152 Hom.: 0 Cov.: 32

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

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

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The 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;.;.
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

Other links and lift over

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