chr9-15465567-C-G

Variant names:

• chr9-15465567-C-G
• rs768464354
• NM_033222.5:c.1546G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033222.5(PSIP1):​c.1546G>C​(p.Glu516Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,433,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E516D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: PSIP1 NM_033222.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

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]

SNAPC3 (HGNC:11136): (small nuclear RNA activating complex polypeptide 3) Predicted to enable RNA polymerase III type 3 promoter sequence-specific DNA binding activity and bent DNA binding activity. Predicted to contribute to RNA polymerase II cis-regulatory region sequence-specific DNA binding activity and core promoter sequence-specific DNA binding activity. Predicted to be involved in snRNA transcription by RNA polymerase II and snRNA transcription by RNA polymerase III. Located in nuclear body and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23892614).
• BS2: High AC in GnomAdExome4 at 73 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033222.5. 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
	PSIP1	NM_033222.5	MANE Select	c.1546G>C	p.Glu516Gln	missense	Exon 16 of 16	NP_150091.2
	PSIP1	NM_001128217.3		c.1546G>C	p.Glu516Gln	missense	Exon 16 of 16	NP_001121689.1	O75475-1
	SNAPC3	NM_001369648.2		c.*3900C>G		3_prime_UTR	Exon 9 of 9	NP_001356577.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSIP1	ENST00000380733.9	TSL:1 MANE Select	c.1546G>C	p.Glu516Gln	missense	Exon 16 of 16	ENSP00000370109.4	O75475-1
	PSIP1	ENST00000380738.8	TSL:1	c.1546G>C	p.Glu516Gln	missense	Exon 16 of 16	ENSP00000370114.4	O75475-1
	SNAPC3	ENST00000610884.4	TSL:1	c.*806C>G		3_prime_UTR	Exon 12 of 12	ENSP00000483273.1	Q92966

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000205 AC: 5 AN: 244322 AF XY: 0.0000303

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000509 AC: 73 AN: 1433108 Hom.: 0 Cov.: 29 AF XY: 0.0000560 AC XY: 40 AN XY: 714134

African (AFR) AF: 0.00 AC: 0 AN: 32584

American (AMR) AF: 0.00 AC: 0 AN: 42880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39296

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000633 AC: 69 AN: 1089648

Other (OTH) AF: 0.0000504 AC: 3 AN: 59468

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000547

EpiControl AF: 0.00

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	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.23
Sift	Uncertain	0.014	D
Sift4G	Benign	0.53	T
Polyphen		0.99	D
Vest4		0.19
MVP		0.50
MPC		0.15
ClinPred		0.25	T
GERP RS		5.9
Varity_R		0.14
gMVP		0.11
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs768464354; hg19: chr9-15465565;