10-77794909-T-G

Position:

• chr10-77794909-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004747.4(DLG5):​c.5486A>C​(p.His1829Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLG5 NM_004747.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.67

Genes affected

DLG5 (HGNC:2904): (discs large MAGUK scaffold protein 5) This gene encodes a member of the family of discs large (DLG) homologs, a subset of the membrane-associated guanylate kinase (MAGUK) superfamily. The MAGUK proteins are composed of a catalytically inactive guanylate kinase domain, in addition to PDZ and SH3 domains, and are thought to function as scaffolding molecules at sites of cell-cell contact. The protein encoded by this gene localizes to the plasma membrane and cytoplasm, and interacts with components of adherens junctions and the cytoskeleton. It is proposed to function in the transmission of extracellular signals to the cytoskeleton and in the maintenance of epithelial cell structure. Alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG5	NM_004747.4	c.5486A>C	p.His1829Pro	missense_variant	30/32	ENST00000372391.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG5	ENST00000372391.7	c.5486A>C	p.His1829Pro	missense_variant	30/32	1	NM_004747.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Richard Lifton Laboratory, Yale University School of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.90
MutPred		0.58		.;Loss of catalytic residue at M1831 (P = 0.0755);
MVP		0.77
MPC		0.90
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.92

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: rs386352298; hg19: chr10-79554667;