chr2-113183213-G-A

Position:

• chr2-113183213-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012455.3(PSD4):​c.757G>A​(p.Ala253Thr) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PSD4 NM_012455.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61

Genes affected

PSD4 (HGNC:19096): (pleckstrin and Sec7 domain containing 4) Predicted to enable guanyl-nucleotide exchange factor activity and phospholipid binding activity. Predicted to be involved in regulation of ARF protein signal transduction and regulation of catalytic activity. Located in ruffle membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.08104512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSD4	NM_012455.3	c.757G>A	p.Ala253Thr	missense_variant	2/17	ENST00000245796.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSD4	ENST00000245796.11	c.757G>A	p.Ala253Thr	missense_variant	2/17	1	NM_012455.3	P3
PSD4	ENST00000441564.7	c.757G>A	p.Ala253Thr	missense_variant	2/17	1		A2
PSD4	ENST00000418251.6	n.943G>A		non_coding_transcript_exon_variant	2/16	5
PSD4	ENST00000485525.5	n.84-1744G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.757G>A (p.A253T) alteration is located in exon 2 (coding exon 1) of the PSD4 gene. This alteration results from a G to A substitution at nucleotide position 757, causing the alanine (A) at amino acid position 253 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0068	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.094
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.36	T;T
Polyphen		0.0010	B;B
Vest4		0.071
MutPred		0.17		Gain of phosphorylation at A253 (P = 0.0388);Gain of phosphorylation at A253 (P = 0.0388);
MVP		0.11
MPC		0.089
ClinPred		0.67	D
GERP RS		5.8
Varity_R		0.11
gMVP		0.040

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-113940790;