Genetic Variant NM_001321075.3:c.2058G>A (chr17-7191277-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001321075.3(DLG4):c.2058G>A(p.Glu686Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,948 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00059 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

DLG4
NM_001321075.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.61

Variant links:

Genes affected

DLG4 (HGNC:2903): (discs large MAGUK scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DLG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 17-7191277-C-T is Benign according to our data. Variant chr17-7191277-C-T is described in ClinVar as [Benign]. Clinvar id is 3041247.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=1.62 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000591 (90/152302) while in subpopulation SAS AF= 0.0184 (89/4826). AF 95% confidence interval is 0.0153. There are 1 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3 link	c.2058G>A	p.Glu686Glu	synonymous_variant	Exon 19 of 20	ENST00000399506.9	NP_001308004.1	P78352-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLG4	ENST00000399506.9 link	c.2058G>A	p.Glu686Glu	synonymous_variant	Exon 19 of 20	2	NM_001321075.3	ENSP00000382425.2	P78352-1
DLG4	ENST00000648172.8 link	c.2187G>A	p.Glu729Glu	synonymous_variant	Exon 21 of 22			ENSP00000497806.3	P78352-2
DLG4	ENST00000648896.1 link	c.2157G>A	p.Glu719Glu	synonymous_variant	Exon 19 of 20			ENSP00000497546.1	A0A3B3ISQ5
DLG4	ENST00000649520.1 link	c.1878G>A	p.Glu626Glu	synonymous_variant	Exon 18 of 19			ENSP00000497647.1	B7Z647
DLG4	ENST00000491753.2 link	n.*73G>A		non_coding_transcript_exon_variant	Exon 20 of 21	2		ENSP00000467897.2	B7Z3U2
DLG4	ENST00000491753.2 link	n.*73G>A		3_prime_UTR_variant	Exon 20 of 21	2		ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00208

AC:

519

AN:

249220

Hom.:

AF XY:

0.00285

AC XY:

386

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0167

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.00107

AC:

1567

AN:

1461646

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1144

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0173

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000591

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0184

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.000110

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DLG4-related disorder

Benign:1

Dec 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

7.7

DANN

Benign

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over