20-36432210-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.493G>A(p.Gly165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,120 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (10 hom.)
• Consequence: DLGAP4 NM_001365621.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.28

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=0.0046290755).
• BP6: Variant 20-36432210-G-A is Benign according to our data. Variant chr20-36432210-G-A is described in ClinVar as [Benign]. Clinvar id is 781497.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00701 (1069/152388) while in subpopulation AFR AF= 0.0234 (972/41598). AF 95% confidence interval is 0.0221. There are 11 homozygotes in gnomad4. There are 517 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1066 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLGAP4	NM_001365621.2	c.493G>A	p.Gly165Ser	missense_variant	3/13	ENST00000339266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLGAP4	ENST00000339266.10	c.493G>A	p.Gly165Ser	missense_variant	3/13	5	NM_001365621.2
DLGAP4	ENST00000373913.7	c.493G>A	p.Gly165Ser	missense_variant	3/13	1
DLGAP4	ENST00000373907.6	c.493G>A	p.Gly165Ser	missense_variant	2/12	5

Frequencies

GnomAD3 genomes AF: 0.00700 AC: 1066 AN: 152270 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00187 AC: 469 AN: 250622 Hom.: 3 AF XY: 0.00139 AC XY: 189 AN XY: 135660

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000705 AC: 1030 AN: 1461732 Hom.: 10 Cov.: 31 AF XY: 0.000613 AC XY: 446 AN XY: 727192

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00701 AC: 1069 AN: 152388 Hom.: 11 Cov.: 32 AF XY: 0.00694 AC XY: 517 AN XY: 74518

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00131 Hom.: 2

Bravo AF: 0.00845

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.34	N
MetaRNN	Benign	0.0046	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.060	N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.21
MVP		0.32
MPC		0.80
ClinPred		0.0072	T
GERP RS		2.1
Varity_R		0.038
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74346057; hg19: chr20-35060613; COSMIC: COSV99042891;