10-77796543-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004747.4(DLG5):c.5216T>C(p.Leu1739Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,614,154 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (25 hom.)
• Consequence: DLG5 NM_004747.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.51

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064600706).
• BP6: Variant 10-77796543-A-G is Benign according to our data. Variant chr10-77796543-A-G is described in ClinVar as [Benign]. Clinvar id is 776519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1574/152326) while in subpopulation AFR AF= 0.0355 (1474/41566). AF 95% confidence interval is 0.034. There are 25 homozygotes in gnomad4. There are 737 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1564 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG5	NM_004747.4	c.5216T>C	p.Leu1739Pro	missense_variant	28/32	ENST00000372391.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG5	ENST00000372391.7	c.5216T>C	p.Leu1739Pro	missense_variant	28/32	1	NM_004747.4	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1564 AN: 152208 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00264 AC: 664 AN: 251078 Hom.: 8 AF XY: 0.00195 AC XY: 264 AN XY: 135726

Gnomad AFR exome AF: 0.0341

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00112 AC: 1635 AN: 1461828 Hom.: 25 Cov.: 32 AF XY: 0.000968 AC XY: 704 AN XY: 727214

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.0103 AC: 1574 AN: 152326 Hom.: 25 Cov.: 33 AF XY: 0.00989 AC XY: 737 AN XY: 74484

Gnomad4 AFR AF: 0.0355

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00180 Hom.: 5

Bravo AF: 0.0114

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0340 AC: 150

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00338 AC: 410

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.0065	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.078
Sift	Benign	0.26	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0010	.;B
Vest4		0.26
MVP		0.26
MPC		0.38
ClinPred		0.020	T
GERP RS		3.6
Varity_R		0.072
gMVP		0.69

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: rs74140333; hg19: chr10-79556301;