1-35192745-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005066.3(SFPQ):c.305C>G(p.Pro102Arg) 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. 12/21 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)
• Consequence: SFPQ NM_005066.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

Genes affected

SFPQ (HGNC:10774): (splicing factor proline and glutamine rich) Enables DNA binding activity; histone deacetylase binding activity; and protein homodimerization activity. Involved in several processes, including alternative mRNA splicing, via spliceosome; positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; and regulation of transcription by RNA polymerase II. Acts upstream of or within double-strand break repair via homologous recombination. Located in chromatin; nuclear matrix; and paraspeckles. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30554667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFPQ	NM_005066.3	c.305C>G	p.Pro102Arg	missense_variant	1/10	ENST00000357214.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFPQ	ENST00000357214.6	c.305C>G	p.Pro102Arg	missense_variant	1/10	1	NM_005066.3	P1
SFPQ	ENST00000696553.1	c.368C>G	p.Pro123Arg	missense_variant	1/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 20, 2022

The c.305C>G (p.P102R) alteration is located in exon 1 (coding exon 1) of the SFPQ gene. This alteration results from a C to G substitution at nucleotide position 305, causing the proline (P) at amino acid position 102 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.95	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.039
Sift4G	Uncertain	0.051	T
Polyphen		0.69	P
Vest4		0.29
MutPred		0.37		Loss of glycosylation at P102 (P = 7e-04);
MVP		0.62
MPC		0.99
ClinPred		0.47	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.13
gMVP		0.16

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: rs1181249857; hg19: chr1-35658346;