X-70445292-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_021120.4(DLG3):c.91G>A(p.Gly31Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,164,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 96 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G31G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.00029 (0 hom. 94 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.87

Genes affected

DLG3 (HGNC:2902): (discs large MAGUK scaffold protein 3) This gene encodes a member of the membrane-associated guanylate kinase protein family. The encoded protein may play a role in clustering of NMDA receptors at excitatory synapses. It may also negatively regulate cell proliferation through interaction with the C-terminal region of the adenomatosis polyposis coli tumor suppressor protein. Mutations in this gene have been associated with X-linked cognitive disability. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14971825).
• BP6: Variant X-70445292-G-A is Benign according to our data. Variant chrX-70445292-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2346213.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000141 (16/113351) while in subpopulation NFE AF= 0.000263 (14/53315). AF 95% confidence interval is 0.000158. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG3	NM_021120.4	c.91G>A	p.Gly31Ser	missense_variant	1/19	ENST00000374360.8
DLG3	XM_006724625.3	c.91G>A	p.Gly31Ser	missense_variant	1/20
DLG3	XM_011530883.2	c.91G>A	p.Gly31Ser	missense_variant	1/19
DLG3	XM_006724626.3	c.91G>A	p.Gly31Ser	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG3	ENST00000374360.8	c.91G>A	p.Gly31Ser	missense_variant	1/19	1	NM_021120.4
DLG3	ENST00000194900.8	c.91G>A	p.Gly31Ser	missense_variant	1/21	5		P1
DLG3	ENST00000463252.5	n.157G>A		non_coding_transcript_exon_variant	1/19	5

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 16 AN: 113351 Hom.: 0 Cov.: 24 AF XY: 0.0000564 AC XY: 2 AN XY: 35491

Gnomad AFR AF: 0.0000319

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: 0.000263

Gnomad OTH AF: 0.000651

GnomAD3 exomes AF: 0.000128 AC: 13 AN: 101387 Hom.: 0 AF XY: 0.000110 AC XY: 4 AN XY: 36221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000516

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000285 AC: 300 AN: 1050833 Hom.: 0 Cov.: 31 AF XY: 0.000274 AC XY: 94 AN XY: 343209

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000714

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: 0.000360

Gnomad4 OTH exome AF: 0.0000676

GnomAD4 genome AF: 0.000141 AC: 16 AN: 113351 Hom.: 0 Cov.: 24 AF XY: 0.0000564 AC XY: 2 AN XY: 35491

Gnomad4 AFR AF: 0.0000319

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: 0.000263

Gnomad4 OTH AF: 0.000651

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.000113

ExAC AF: 0.0000775 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.51
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.040	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.28	N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.23	T;D
Polyphen		1.0	.;D
Vest4		0.27
MVP		0.73
MPC		0.71
ClinPred		0.25	T
GERP RS		3.8
Varity_R		0.38
gMVP		0.40

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: rs771173179; hg19: chrX-69665142;