17-7190812-T-C

Position:

• chr17-7190812-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001321075.3(DLG4):​c.2071A>G​(p.Ile691Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DLG4 NM_001321075.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DLG4. . Gene score misZ 4.933 (greater than the threshold 3.09). Trascript score misZ 4.8337 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, intellectual developmental disorder 62.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17666313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.2071A>G	p.Ile691Val	missense_variant, splice_region_variant	20/20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.2071A>G	p.Ile691Val	missense_variant, splice_region_variant	20/20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.8	c.2200A>G	p.Ile734Val	missense_variant, splice_region_variant	22/22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2170A>G	p.Ile724Val	missense_variant, splice_region_variant	20/20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1891A>G	p.Ile631Val	missense_variant, splice_region_variant	19/19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.*86A>G		splice_region_variant, non_coding_transcript_exon_variant	21/21	2		ENSP00000467897.2
DLG4	ENST00000491753.2	n.*86A>G		3_prime_UTR_variant	21/21	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151680 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461114 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726870

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151680 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74076

Gnomad4 AFR AF: 0.0000970

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000851 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.2200A>G (p.I734V) alteration is located in exon 22 (coding exon 22) of the DLG4 gene. This alteration results from a A to G substitution at nucleotide position 2200, causing the isoleucine (I) at amino acid position 734 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.28	.;.;T;T;T;.;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;D;D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.19	.;.;N;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.37	.;N;N;.;.;.;.;.
REVEL	Benign	0.046
Sift	Benign	0.45	.;T;T;.;.;.;.;.
Sift4G	Benign	0.63	.;T;T;.;.;.;.;.
Polyphen		0.0	B;.;B;.;B;.;.;.
Vest4		0.11, 0.12
MutPred		0.57		.;.;Loss of catalytic residue at I691 (P = 0.1096);.;.;.;.;.;
MVP		0.54
MPC		1.0
ClinPred		0.39	T
GERP RS		4.5
Varity_R		0.045
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs985891095; hg19: chr17-7094131;