chr17-7191277-C-T

Variant names:

• chr17-7191277-C-T
• rs560100344
• NM_001321075.3:c.2058G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

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
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.61
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder 62

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• 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	c.2058G>A	p.Glu686Glu	synonymous_variant	Exon 19 of 20	ENST00000399506.9	NP_001308004.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152184 Hom.: 1 Cov.: 31

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

GnomAD2 exomes AF: 0.00208 AC: 519 AN: 249220 AF XY: 0.00285

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 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.: 29 Cov.: 31 AF XY: 0.00157 AC XY: 1144 AN XY: 727108

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0173 AC: 1492 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5762

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111836

Other (OTH) AF: 0.000795 AC: 48 AN: 60368

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152302 Hom.: 1 Cov.: 31 AF XY: 0.000900 AC XY: 67 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0184 AC: 89 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000110

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

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
PhyloP100		1.6
Mutation Taster		=100/0	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: rs560100344; hg19: chr17-7094596;