Genetic Variant NM_001321075.3:c.1994T>C (chr17-7191341-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001321075.3(DLG4):c.1994T>C(p.Ile665Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,688 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: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DLG4
NM_001321075.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.82

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19610506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3 link	c.1994T>C	p.Ile665Thr	missense_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.1994T>C	p.Ile665Thr	missense_variant	Exon 19 of 20	2	NM_001321075.3	ENSP00000382425.2	P78352-1
DLG4	ENST00000648172.8 link	c.2123T>C	p.Ile708Thr	missense_variant	Exon 21 of 22			ENSP00000497806.3	P78352-2
DLG4	ENST00000648896.1 link	c.2093T>C	p.Ile698Thr	missense_variant	Exon 19 of 20			ENSP00000497546.1	A0A3B3ISQ5
DLG4	ENST00000649520.1 link	c.1814T>C	p.Ile605Thr	missense_variant	Exon 18 of 19			ENSP00000497647.1	B7Z647
DLG4	ENST00000491753.2 link	n.*9T>C		non_coding_transcript_exon_variant	Exon 20 of 21	2		ENSP00000467897.2	B7Z3U2
DLG4	ENST00000491753.2 link	n.*9T>C		3_prime_UTR_variant	Exon 20 of 21	2		ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151962

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

.;.;T;T;T;.;T;.

Eigen

Benign

0.029

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.94

D;D;D;.;D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.20

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;.;L;.;.;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.1

.;N;N;.;.;.;.;.

REVEL

Benign

0.090

Sift

Uncertain

0.0060

.;D;D;.;.;.;.;.

Sift4G

Uncertain

0.039

.;D;D;.;.;.;.;.

Polyphen

0.013

B;.;B;.;B;.;.;.

Vest4

0.43, 0.43

MutPred

0.52

.;.;Loss of stability (P = 0.0126);.;.;.;.;.;

MVP

0.34

MPC

1.5

ClinPred

0.85

GERP RS

5.3

Varity_R

0.077

gMVP

0.78

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