10-77806906-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004747.4(DLG5):c.4819G>A(p.Asp1607Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,613,758 control chromosomes in the GnomAD database, including 24 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (23 hom.)
• Consequence: DLG5 NM_004747.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.36

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006292641).
• BP6: Variant 10-77806906-C-T is Benign according to our data. Variant chr10-77806906-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 728461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 563 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG5	NM_004747.4	c.4819G>A	p.Asp1607Asn	missense_variant	26/32	ENST00000372391.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG5	ENST00000372391.7	c.4819G>A	p.Asp1607Asn	missense_variant	26/32	1	NM_004747.4	P1

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 563 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00581

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00333 AC: 836 AN: 251408 Hom.: 3 AF XY: 0.00322 AC XY: 437 AN XY: 135870

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00499

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00456 AC: 6660 AN: 1461412 Hom.: 23 Cov.: 36 AF XY: 0.00443 AC XY: 3221 AN XY: 726922

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00496

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00540

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00369 AC: 562 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00341 AC XY: 254 AN XY: 74492

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00581

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00456 Hom.: 4

Bravo AF: 0.00419

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00358 AC: 434

EpiCase AF: 0.00442

EpiControl AF: 0.00510

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	DLG5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.14
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.017	.;B
Vest4		0.16
MVP		0.36
MPC		0.25
ClinPred		0.033	T
GERP RS		5.9
Varity_R		0.084
gMVP		0.22

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: rs147733899; hg19: chr10-79566664; COSMIC: COSV100968012;