20-36432450-G-A

Variant summary

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

The NM_001365621.2(DLGAP4):c.733G>A(p.Ala245Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,822 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (33 hom.)
• Consequence: DLGAP4 NM_001365621.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.60

Genes affected

DLGAP4 (HGNC:24476): (DLG associated protein 4) The product of this gene is a membrane-associated guanylate kinase found at the postsynaptic density in neuronal cells. It is a signaling molecule that can interact with potassium channels and receptors, as well as other signaling molecules. The protein encoded by this gene can interact with PSD-95 through its guanylate kinase domain and may be involved in clustering PSD-95 in the postsynaptic density region. The encoded protein is one of at least four similar proteins that have been found. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009884894).
• BP6: Variant 20-36432450-G-A is Benign according to our data. Variant chr20-36432450-G-A is described in ClinVar as [Benign]. Clinvar id is 790889.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00144 (220/152292) while in subpopulation SAS AF= 0.0188 (91/4828). AF 95% confidence interval is 0.0157. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLGAP4	NM_001365621.2	c.733G>A	p.Ala245Thr	missense_variant	3/13	ENST00000339266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLGAP4	ENST00000339266.10	c.733G>A	p.Ala245Thr	missense_variant	3/13	5	NM_001365621.2
DLGAP4	ENST00000373913.7	c.733G>A	p.Ala245Thr	missense_variant	3/13	1
DLGAP4	ENST00000373907.6	c.733G>A	p.Ala245Thr	missense_variant	2/12	5

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00313 AC: 781 AN: 249920 Hom.: 8 AF XY: 0.00409 AC XY: 554 AN XY: 135556

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00218 AC: 3182 AN: 1461530 Hom.: 33 Cov.: 31 AF XY: 0.00274 AC XY: 1993 AN XY: 727050

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.000264

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00166 AC XY: 124 AN XY: 74486

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.000892

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00136

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 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0099	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.039	D;T;D;T
Polyphen		0.97	D;.;D;.
Vest4		0.56
MVP		0.27
MPC		0.92
ClinPred		0.066	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.36

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: rs146757517; hg19: chr20-35060853; COSMIC: COSV59419038;