chr6-144423624-A-G

Position:

• chr6-144423624-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007124.3(UTRN):​c.310A>G​(p.Asn104Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UTRN NM_007124.3 missense, splice_region
• Scores: Splicing: ADA: 0.4948
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UTRN	NM_007124.3	c.310A>G	p.Asn104Asp	missense_variant, splice_region_variant	5/75	ENST00000367545.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UTRN	ENST00000367545.8	c.310A>G	p.Asn104Asp	missense_variant, splice_region_variant	5/75	5	NM_007124.3	P1
UTRN	ENST00000421035.2	c.325A>G	p.Asn109Asp	missense_variant, splice_region_variant	4/6	2
UTRN	ENST00000628146.2	c.283A>G	p.Asn95Asp	missense_variant, splice_region_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Apr 23, 2024

The c.310A>G (p.N104D) alteration is located in exon 4 (coding exon 4) of the UTRN gene. This alteration results from a A to G substitution at nucleotide position 310, causing the asparagine (N) at amino acid position 104 to be replaced by an aspartic acid (D). 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	0.099
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.87	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D;.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0090	D;.;T
Sift4G	Benign	0.56	.;T;T
Polyphen		0.50	P;.;.
Vest4		0.39
MutPred		0.57		Gain of catalytic residue at N104 (P = 0.0202);.;.;
MVP		0.79
MPC		0.17
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.58
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.49
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-144744760;