9-15474024-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033222.5(PSIP1):c.843T>A(p.Asp281Glu) 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: 32)
  • Exomes 𝑓: 0.0000014 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSIP1 NM_033222.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.884

Genes affected

PSIP1 (HGNC:9527): (PC4 and SRSF1 interacting protein 1) Enables DNA-binding transcription factor binding activity; chromatin binding activity; and transcription coactivator activity. Involved in mRNA 5'-splice site recognition and positive regulation of transcription by RNA polymerase II. Located in heterochromatin; nuclear periphery; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062434077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSIP1	NM_033222.5	c.843T>A	p.Asp281Glu	missense_variant	9/16	ENST00000380733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSIP1	ENST00000380733.9	c.843T>A	p.Asp281Glu	missense_variant	9/16	1	NM_033222.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1460592 Hom.: 1 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726626

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

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

Aug 02, 2021

The c.843T>A (p.D281E) alteration is located in exon 9 (coding exon 8) of the PSIP1 gene. This alteration results from a T to A substitution at nucleotide position 843, causing the aspartic acid (D) at amino acid position 281 to be replaced by a glutamic acid (E). 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	0.074
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	15
Dann	Benign	0.82
DEOGEN2	Benign	0.049	T;T;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.062	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.63	N;N;N;N;N
MutationTaster	Benign	0.97	N;N;N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.77	N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.87	T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T
Polyphen		0.0010	B;B;.;B;B
Vest4		0.045
MutPred		0.091		Gain of ubiquitination at K286 (P = 0.1062);Gain of ubiquitination at K286 (P = 0.1062);Gain of ubiquitination at K286 (P = 0.1062);Gain of ubiquitination at K286 (P = 0.1062);Gain of ubiquitination at K286 (P = 0.1062);
MVP		0.48
MPC		0.13
ClinPred		0.32	T
GERP RS		4.2
Varity_R		0.045
gMVP		0.024

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr9-15474022;