Genetic Variant DLGAP1:p.Ala173Gly (chr18-3879551-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004746.4(DLGAP1):c.518C>G(p.Ala173Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A173V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DLGAP1
NM_004746.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.48

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04524985).

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.518C>G	p.Ala173Gly	missense	Exon 4 of 13	NP_004737.2
DLGAP1	NM_001398525.1		c.518C>G	p.Ala173Gly	missense	Exon 4 of 14	NP_001385454.1
DLGAP1	NM_001398526.1		c.518C>G	p.Ala173Gly	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.518C>G	p.Ala173Gly	missense	Exon 4 of 13	ENSP00000316377.3	O14490-1
DLGAP1	ENST00000498188.5	TSL:1	n.526C>G		non_coding_transcript_exon	Exon 1 of 5
DLGAP1-AS3	ENST00000577649.1	TSL:1	n.112+1260G>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446342

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719568

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000300

AC:

AN:

33374

American (AMR)

AF:

0.00

AC:

AN:

44420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25738

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

85516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109518

Other (OTH)

AF:

0.00

AC:

AN:

60110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.027

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.82

M_CAP

Benign

0.0034

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.85

PhyloP100

5.5

PrimateAI

Benign

0.34

PROVEAN

Benign

0.92

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MutPred

0.098

Loss of stability (P = 0.0915)

MVP

0.30

MPC

0.37

ClinPred

0.098

GERP RS

4.9

Varity_R

0.067

gMVP

0.073

Mutation Taster

=94/6

polymorphism

(source)

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