chr10-102404618-G-A

Position:

• chr10-102404618-G-A

Variant summary

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

The NM_002779.5(PSD):​c.2665C>T​(p.Pro889Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PSD NM_002779.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

PSD (HGNC:9507): (pleckstrin and Sec7 domain containing) This gene encodes a Plekstrin homology and SEC7 domains-containing protein that functions as a guanine nucleotide exchange factor. The encoded protein regulates signal transduction by activating ADP-ribosylation factor 6. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

PSD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSD	NM_002779.5	c.2665C>T	p.Pro889Ser	missense_variant	15/17	ENST00000020673.6	NP_002770.3
PSD	NM_001270965.2	c.2665C>T	p.Pro889Ser	missense_variant	16/18		NP_001257894.1
PSD	NM_001270966.2	c.1528C>T	p.Pro510Ser	missense_variant	16/18		NP_001257895.1
PSD	NR_073110.2	n.957C>T		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSD	ENST00000020673.6	c.2665C>T	p.Pro889Ser	missense_variant	15/17	1	NM_002779.5	ENSP00000020673.5
PSD	ENST00000406432.5	c.2665C>T	p.Pro889Ser	missense_variant	16/18	1		ENSP00000384830.1
PSD	ENST00000611678.4	c.1528C>T	p.Pro510Ser	missense_variant	16/18	1		ENSP00000481250.1
PSD	ENST00000479172.5	n.*27C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459698 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726096

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 17, 2021

The c.2665C>T (p.P889S) alteration is located in exon 15 (coding exon 14) of the PSD gene. This alteration results from a C to T substitution at nucleotide position 2665, causing the proline (P) at amino acid position 889 to be replaced by a serine (S). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	.;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	2.9	.;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.2	.;D;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.76
MutPred		0.33		.;Gain of phosphorylation at P889 (P = 0.0209);Gain of phosphorylation at P889 (P = 0.0209);
MVP		0.49
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.78

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: rs2061338687; hg19: chr10-104164375;