Genetic Variant DLGAP1:p.Thr261Ala (chr18-3879288-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_004746.4(DLGAP1):c.781A>G(p.Thr261Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,444,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

DLGAP1
NM_004746.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.67

Publications

0 publications found

Variant links:

Genes affected

DLGAP1 (HGNC:2905): (DLG associated protein 1) Predicted to enable molecular adaptor activity. Predicted to be a structural constituent of postsynaptic density. Predicted to be involved in several processes, including aggresome assembly; regulation of postsynaptic neurotransmitter receptor activity; and regulation of proteasomal protein catabolic process. Predicted to be located in plasma membrane. Predicted to be part of postsynaptic density. Predicted to be active in glutamatergic synapse and postsynaptic density, intracellular component. [provided by Alliance of Genome Resources, Apr 2022]

DLGAP1 links:

DLGAP1-AS3 (HGNC:27317): (DLGAP1 antisense RNA 3)

DLGAP1-AS3 links:

LOC124904238 (HGNC:):

LOC124904238 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16168734).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004746.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLGAP1	NM_004746.4	MANE Select	c.781A>G	p.Thr261Ala	missense	Exon 4 of 13	NP_004737.2
DLGAP1	NM_001398525.1		c.781A>G	p.Thr261Ala	missense	Exon 4 of 14	NP_001385454.1
DLGAP1	NM_001398526.1		c.781A>G	p.Thr261Ala	missense	Exon 4 of 14	NP_001385455.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLGAP1	ENST00000315677.8	TSL:5 MANE Select	c.781A>G	p.Thr261Ala	missense	Exon 4 of 13	ENSP00000316377.3	O14490-1
DLGAP1	ENST00000498188.5	TSL:1	n.789A>G		non_coding_transcript_exon	Exon 1 of 5
DLGAP1-AS3	ENST00000577649.1	TSL:1	n.112+997T>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000852

AC:

AN:

234758

AF XY:

0.00000793

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1444350

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

716640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33140

American (AMR)

AF:

0.00

AC:

AN:

43038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24718

East Asian (EAS)

AF:

0.0000758

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

83074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1102944

Other (OTH)

AF:

0.00

AC:

AN:

59572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.035

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.064

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

M_CAP

Benign

0.0070

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

4.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.36

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.021

Vest4

0.64

MutPred

0.31

Loss of phosphorylation at T261 (P = 0.0766)

MVP

0.89

MPC

0.37

ClinPred

0.13

GERP RS

5.5

Varity_R

0.15

gMVP

0.20

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over