NM_001080418.3:c.133C>A

Variant names:

• chr1-34905251-G-T
• rs567109248
• NM_001080418.3:c.133C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001080418.3(DLGAP3):​c.133C>A​(p.Pro45Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,592,980 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P45H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: DLGAP3 NM_001080418.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.88
• Publications: 2 publications found

Genes affected

DLGAP3 (HGNC:30368): (DLG associated protein 3) Predicted to enable PDZ domain binding activity; molecular adaptor activity; and scaffold protein binding activity. Predicted to be involved in protein-containing complex assembly and regulation of postsynaptic neurotransmitter receptor activity. Predicted to be located in synapse. Predicted to be part of postsynaptic density. Predicted to be active in several cellular components, including cholinergic synapse; glutamatergic synapse; and neuromuscular junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076347888).
• BP6: Variant 1-34905251-G-T is Benign according to our data. Variant chr1-34905251-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 722226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLGAP3	NM_001080418.3	c.133C>A	p.Pro45Thr	missense_variant	Exon 3 of 12	ENST00000373347.6	NP_001073887.1
DLGAP3	XM_011541879.3	c.133C>A	p.Pro45Thr	missense_variant	Exon 4 of 13		XP_011540181.1
DLGAP3	XM_047426631.1	c.133C>A	p.Pro45Thr	missense_variant	Exon 3 of 12		XP_047282587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLGAP3	ENST00000373347.6	c.133C>A	p.Pro45Thr	missense_variant	Exon 3 of 12	5	NM_001080418.3	ENSP00000362444.1
DLGAP3	ENST00000235180.4	c.133C>A	p.Pro45Thr	missense_variant	Exon 1 of 10	2		ENSP00000235180.4
DLGAP3	ENST00000495979.1	n.388C>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00445

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000313 AC: 64 AN: 204670 AF XY: 0.000351

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000656

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00376

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 157 AN: 1440734 Hom.: 2 Cov.: 33 AF XY: 0.000102 AC XY: 73 AN XY: 714466

African (AFR) AF: 0.00 AC: 0 AN: 33212

American (AMR) AF: 0.0000481 AC: 2 AN: 41562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25520

East Asian (EAS) AF: 0.00295 AC: 115 AN: 38942

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5478

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102238

Other (OTH) AF: 0.000655 AC: 39 AN: 59566

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74434

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00446 AC: 23 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000223

ExAC AF: 0.000233 AC: 28

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.0024
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T;.
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
PhyloP100		3.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.083
Sift	Benign	0.23	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.075	B;B
Vest4		0.43
MutPred		0.29		Gain of phosphorylation at P45 (P = 0.0573);Gain of phosphorylation at P45 (P = 0.0573);
MVP		0.20
MPC		0.88
ClinPred		0.029	T
GERP RS		4.5
PromoterAI		0.0038	Neutral
Varity_R		0.18
gMVP		0.38
Mutation Taster		=86/14	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: rs567109248; hg19: chr1-35370852;