6-144730458-G-C

Variant names:

• chr6-144730458-G-C
• rs4305737
• NM_007124.3:c.7911G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007124.3(UTRN):​c.7911G>C​(p.Glu2637Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E2637E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UTRN NM_007124.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 18 publications found

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]

UTRN Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08824438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UTRN	NM_007124.3	c.7911G>C	p.Glu2637Asp	missense_variant	Exon 54 of 75	ENST00000367545.8	NP_009055.2
UTRN	NM_001375323.1	c.576G>C	p.Glu192Asp	missense_variant	Exon 4 of 25		NP_001362252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UTRN	ENST00000367545.8	c.7911G>C	p.Glu2637Asp	missense_variant	Exon 54 of 75	5	NM_007124.3	ENSP00000356515.3
UTRN	ENST00000367526.8	c.576G>C	p.Glu192Asp	missense_variant	Exon 4 of 25	5		ENSP00000356496.4
UTRN	ENST00000367524.8	c.576G>C	p.Glu192Asp	missense_variant	Exon 4 of 24	3		ENSP00000356494.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		1.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.17
Sift	Benign	0.067	T;T
Sift4G	Pathogenic	0.0	.;T
Vest4		0.48
ClinPred		0.27	T
GERP RS		2.7
Varity_R		0.048
gMVP		0.19
Mutation Taster		=54/46	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

Other links and lift over

dbSNP: rs4305737; hg19: chr6-145051594;