10-77806887-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004747.4(DLG5):c.4838G>A(p.Ser1613Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DLG5 NM_004747.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26953456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG5	NM_004747.4	c.4838G>A	p.Ser1613Asn	missense_variant	26/32	ENST00000372391.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG5	ENST00000372391.7	c.4838G>A	p.Ser1613Asn	missense_variant	26/32	1	NM_004747.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461680 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Aug 04, 2023

The c.4838G>A (p.S1613N) alteration is located in exon 26 (coding exon 26) of the DLG5 gene. This alteration results from a G to A substitution at nucleotide position 4838, causing the serine (S) at amino acid position 1613 to be replaced by an asparagine (N). 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	0.17
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.16
Sift	Benign	0.22	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.021	.;B
Vest4		0.18
MutPred		0.42		.;Loss of ubiquitination at K1615 (P = 0.1016);
MVP		0.33
MPC		0.23
ClinPred		0.84	D
GERP RS		5.9
Varity_R		0.16
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-79566645;