X-70445206-A-C

Variant names:

• chrX-70445206-A-C
• rs1410761133
• NM_021120.4:c.5A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_021120.4(DLG3):​c.5A>C​(p.His2Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,043,050 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000096 (0 hom. 4 hem.)
• Consequence: DLG3 NM_021120.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.84

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a modified_residue N-acetylmethionine (size 0) in uniprot entity DLG3_HUMAN
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG3	NM_021120.4	c.5A>C	p.His2Pro	missense_variant	Exon 1 of 19	ENST00000374360.8	NP_066943.2
DLG3	XM_006724625.3	c.5A>C	p.His2Pro	missense_variant	Exon 1 of 20		XP_006724688.1
DLG3	XM_011530883.2	c.5A>C	p.His2Pro	missense_variant	Exon 1 of 19		XP_011529185.1
DLG3	XM_006724626.3	c.5A>C	p.His2Pro	missense_variant	Exon 1 of 20		XP_006724689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG3	ENST00000374360.8	c.5A>C	p.His2Pro	missense_variant	Exon 1 of 19	1	NM_021120.4	ENSP00000363480.3
DLG3	ENST00000194900.8	c.5A>C	p.His2Pro	missense_variant	Exon 1 of 21	5		ENSP00000194900.4
DLG3	ENST00000463252.5	n.71A>C		non_coding_transcript_exon_variant	Exon 1 of 19	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000101 AC: 1 AN: 99170 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 35486

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 10 AN: 1043050 Hom.: 0 Cov.: 30 AF XY: 0.0000118 AC XY: 4 AN XY: 337816

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000123

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5A>C (p.H2P) alteration is located in exon 1 (coding exon 1) of the DLG3 gene. This alteration results from a A to C substitution at nucleotide position 5, causing the histidine (H) at amino acid position 2 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability, X-linked 90 Uncertain:1

Sep 09, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.94	.;P
Vest4		0.53
MutPred		0.32		Gain of catalytic residue at H2 (P = 0.0066);Gain of catalytic residue at H2 (P = 0.0066);
MVP		0.79
MPC		1.1
ClinPred		0.83	D
GERP RS		4.0
Varity_R		0.56
gMVP		0.73

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

Other links and lift over

dbSNP: rs1410761133; hg19: chrX-69665056;