NM_001365621.2:c.86G>A

Variant names:

• chr20-36431803-G-A
• rs367982678
• NM_001365621.2:c.86G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001365621.2(DLGAP4):​c.86G>A​(p.Arg29His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,542 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: DLGAP4 NM_001365621.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2378565).
• BS2: High AC in GnomAd4 at 30 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365621.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLGAP4	NM_001365621.2	MANE Select	c.86G>A	p.Arg29His	missense	Exon 3 of 13	NP_001352550.1	Q9Y2H0-2
	DLGAP4	NM_014902.6		c.86G>A	p.Arg29His	missense	Exon 3 of 13	NP_055717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLGAP4	ENST00000339266.10	TSL:5 MANE Select	c.86G>A	p.Arg29His	missense	Exon 3 of 13	ENSP00000341633.5	Q9Y2H0-2
	DLGAP4	ENST00000373913.7	TSL:1	c.86G>A	p.Arg29His	missense	Exon 3 of 13	ENSP00000363023.3	Q9Y2H0-1
	DLGAP4	ENST00000373907.6	TSL:5	c.86G>A	p.Arg29His	missense	Exon 2 of 12	ENSP00000363014.2	Q9Y2H0-2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000731 AC: 18 AN: 246260 AF XY: 0.0000749

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461474 Hom.: 1 Cov.: 31 AF XY: 0.000271 AC XY: 197 AN XY: 727026

African (AFR) AF: 0.000299 AC: 10 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000300 AC: 334 AN: 1111894

Other (OTH) AF: 0.000132 AC: 8 AN: 60384

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74252

African (AFR) AF: 0.000217 AC: 9 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000326 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.11	N
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.23	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.70
MPC		0.67
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.060
gMVP		0.62
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs367982678; hg19: chr20-35060206; COSMIC: COSV59421357;