NM_004746.4:c.2176A>T

Variant names:

• chr18-3534497-T-A
• rs2052212754
• NM_004746.4:c.2176A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004746.4(DLGAP1):​c.2176A>T​(p.Met726Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLGAP1 NM_004746.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.620
• Publications: 0 publications found

Genes affected

DLGAP1 (HGNC:2905): (DLG associated protein 1) Predicted to enable molecular adaptor activity. Predicted to be a structural constituent of postsynaptic density. Predicted to be involved in several processes, including aggresome assembly; regulation of postsynaptic neurotransmitter receptor activity; and regulation of proteasomal protein catabolic process. Predicted to be located in plasma membrane. Predicted to be part of postsynaptic density. Predicted to be active in glutamatergic synapse and postsynaptic density, intracellular component. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047316343).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004746.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLGAP1	NM_004746.4	MANE Select	c.2176A>T	p.Met726Leu	missense	Exon 10 of 13	NP_004737.2
	DLGAP1	NM_001398525.1		c.2206A>T	p.Met736Leu	missense	Exon 11 of 14	NP_001385454.1
	DLGAP1	NM_001398526.1		c.2206A>T	p.Met736Leu	missense	Exon 11 of 14	NP_001385455.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLGAP1	ENST00000315677.8	TSL:5 MANE Select	c.2176A>T	p.Met726Leu	missense	Exon 10 of 13	ENSP00000316377.3	O14490-1
	DLGAP1	ENST00000400147.6	TSL:1	c.1270A>T	p.Met424Leu	missense	Exon 7 of 10	ENSP00000383011.2	O14490-2
	DLGAP1	ENST00000400145.6	TSL:1	c.1270A>T	p.Met424Leu	missense	Exon 7 of 9	ENSP00000383010.2	O14490-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.5
DANN	Benign	0.62
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.51	N
PhyloP100		0.62
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.063
Sift	Benign	0.40	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.36		Gain of sheet (P = 0.1945)
MVP		0.24
MPC		0.83
ClinPred		0.36	T
GERP RS		2.3
Varity_R		0.13
gMVP		0.26
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs2052212754; hg19: chr18-3534495;