10-77796547-C-T

Position:

• chr10-77796547-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004747.4(DLG5):​c.5212G>A​(p.Ala1738Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,614,120 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: DLG5 NM_004747.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.44

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024555326).
• BP6: Variant 10-77796547-C-T is Benign according to our data. Variant chr10-77796547-C-T is described in ClinVar as [Benign]. Clinvar id is 776520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1704/152316) while in subpopulation AFR AF= 0.0386 (1603/41562). AF 95% confidence interval is 0.037. There are 34 homozygotes in gnomad4. There are 798 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1704 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG5	NM_004747.4	c.5212G>A	p.Ala1738Thr	missense_variant	28/32	ENST00000372391.7	NP_004738.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG5	ENST00000372391.7	c.5212G>A	p.Ala1738Thr	missense_variant	28/32	1	NM_004747.4	ENSP00000361467	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1695 AN: 152198 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0385

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: 0.000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00288 AC: 724 AN: 251022 Hom.: 9 AF XY: 0.00213 AC XY: 289 AN XY: 135682

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.00174

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: 0.000282

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00121 AC: 1773 AN: 1461804 Hom.: 28 Cov.: 32 AF XY: 0.00105 AC XY: 763 AN XY: 727200

Gnomad4 AFR exome AF: 0.0376

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.0112 AC: 1704 AN: 152316 Hom.: 34 Cov.: 33 AF XY: 0.0107 AC XY: 798 AN XY: 74484

Gnomad4 AFR AF: 0.0386

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: 0.000147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000597 Hom.: 2

Bravo AF: 0.0123

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0372 AC: 164

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00365 AC: 443

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Benign	0.75
DEOGEN2	Benign	0.060	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.14	.;N
MutationTaster	Benign	0.86	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.25	N;N
REVEL	Benign	0.048
Sift	Benign	0.36	T;T
Sift4G	Uncertain	0.036	D;D
Polyphen		0.0	.;B
Vest4		0.13
MVP		0.18
MPC		0.23
ClinPred		0.0020	T
GERP RS		2.4
Varity_R		0.018
gMVP		0.28

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: rs74140334; hg19: chr10-79556305;