17-7191962-C-A

Variant names:

• chr17-7191962-C-A
• rs1488126978
• NM_001321075.3:c.1907G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001321075.3(DLG4):​c.1907G>T​(p.Arg636Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,326,878 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: 0.0000015 (0 hom.)
• Consequence: DLG4 NM_001321075.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.618
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a domain Guanylate kinase-like (size 175) in uniprot entity DLG4_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001321075.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3807283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.1907G>T	p.Arg636Leu	missense_variant	Exon 18 of 20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.1907G>T	p.Arg636Leu	missense_variant	Exon 18 of 20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.9	c.2036G>T	p.Arg679Leu	missense_variant	Exon 20 of 22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2006G>T	p.Arg669Leu	missense_variant	Exon 18 of 20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1727G>T	p.Arg576Leu	missense_variant	Exon 17 of 19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.1996-604G>T		intron_variant	Intron 19 of 20	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1326878 Hom.: 0 Cov.: 31 AF XY: 0.00000307 AC XY: 2 AN XY: 651970

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

African (AFR) AF: 0.00 AC: 0 AN: 28220

American (AMR) AF: 0.00 AC: 0 AN: 27580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19758

East Asian (EAS) AF: 0.00 AC: 0 AN: 33920

South Asian (SAS) AF: 0.0000152 AC: 1 AN: 65604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5198

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1043470

Other (OTH) AF: 0.00 AC: 0 AN: 54090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 01, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;.;T;T;T;.;T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.29	N
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.5	.;.;L;.;.;.;.;.;.
PhyloP100		0.62
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	.;D;D;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.0010	.;D;D;.;.;.;.;.;.
Sift4G	Uncertain	0.059	.;T;D;.;.;.;.;.;.
Polyphen		0.99	D;.;P;.;P;.;.;.;.
Vest4		0.49, 0.50
MutPred		0.55		.;.;Loss of MoRF binding (P = 0.0441);.;.;.;.;.;.;
MVP		0.62
MPC		2.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.17
gMVP		0.98
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1488126978; hg19: chr17-7095281;