10-77811115-G-T

Variant names:

• chr10-77811115-G-T
• rs2289310
• NM_004747.4:c.4442C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004747.4(DLG5):​c.4442C>A​(p.Pro1481Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0434 in 1,610,818 control chromosomes in the GnomAD database, including 2,215 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.044 (232 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1983 hom.)
• Consequence: DLG5 NM_004747.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.98
• Publications: 25 publications found

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]

DLG5 Gene-Disease associations (from GenCC):

• Yuksel-Vogel-Bauer syndrome

  Inheritance: AD, AR Classification: LIMITED Submitted by: G2P
• ciliopathy

  Inheritance: AR, AD Classification: LIMITED Submitted by: Franklin by Genoox
• congenital anomaly of kidney and urinary tract

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017066598).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG5	NM_004747.4	c.4442C>A	p.Pro1481Gln	missense_variant	Exon 23 of 32	ENST00000372391.7	NP_004738.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG5	ENST00000372391.7	c.4442C>A	p.Pro1481Gln	missense_variant	Exon 23 of 32	1	NM_004747.4	ENSP00000361467.2

Frequencies

GnomAD3 genomes AF: 0.0444 AC: 6743 AN: 151826 Hom.: 231 Cov.: 32

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.0638

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0451

GnomAD2 exomes AF: 0.0573 AC: 14266 AN: 248976 AF XY: 0.0574

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.0451

Gnomad NFE exome AF: 0.0415

Gnomad OTH exome AF: 0.0612

GnomAD4 exome AF: 0.0433 AC: 63113 AN: 1458876 Hom.: 1983 Cov.: 32 AF XY: 0.0441 AC XY: 32015 AN XY: 725752

African (AFR) AF: 0.0339 AC: 1132 AN: 33422

American (AMR) AF: 0.0462 AC: 2064 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3483 AN: 26102

East Asian (EAS) AF: 0.176 AC: 6972 AN: 39682

South Asian (SAS) AF: 0.0516 AC: 4440 AN: 86092

European-Finnish (FIN) AF: 0.0446 AC: 2340 AN: 52482

Middle Eastern (MID) AF: 0.0878 AC: 400 AN: 4554

European-Non Finnish (NFE) AF: 0.0349 AC: 38811 AN: 1111668

Other (OTH) AF: 0.0576 AC: 3471 AN: 60236

GnomAD4 genome AF: 0.0444 AC: 6753 AN: 151942 Hom.: 232 Cov.: 32 AF XY: 0.0448 AC XY: 3326 AN XY: 74262

African (AFR) AF: 0.0316 AC: 1309 AN: 41464

American (AMR) AF: 0.0476 AC: 726 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 484 AN: 3464

East Asian (EAS) AF: 0.177 AC: 902 AN: 5100

South Asian (SAS) AF: 0.0632 AC: 303 AN: 4794

European-Finnish (FIN) AF: 0.0414 AC: 439 AN: 10604

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0362 AC: 2457 AN: 67940

Other (OTH) AF: 0.0475 AC: 100 AN: 2106

Alfa AF: 0.0447 Hom.: 900

Bravo AF: 0.0471

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.0304 AC: 134

ESP6500EA AF: 0.0422 AC: 363

ExAC AF: 0.0573 AC: 6953

EpiCase AF: 0.0411

EpiControl AF: 0.0392

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.0	.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.0	.;.
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	.;L
PhyloP100		4.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.083
Sift	Benign	0.10	T;T
Sift4G	Uncertain	0.053	T;T
Vest4		0.0
ClinPred		0.011	T
GERP RS		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.29
Mutation Taster		=99/1	polymorphism (auto)

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: rs2289310; hg19: chr10-79570873; COSMIC: COSV64947544; COSMIC: COSV64947544;