1-35190591-G-A

Variant summary

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

The NM_005066.3(SFPQ):c.1322C>T(p.Thr441Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SFPQ NM_005066.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFPQ	NM_005066.3	c.1322C>T	p.Thr441Ile	missense_variant, splice_region_variant	4/10	ENST00000357214.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFPQ	ENST00000357214.6	c.1322C>T	p.Thr441Ile	missense_variant, splice_region_variant	4/10	1	NM_005066.3	P1
SFPQ	ENST00000696553.1	c.1385C>T	p.Thr462Ile	missense_variant, splice_region_variant	4/10
SFPQ	ENST00000470472.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460008 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

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: 0.00

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

Jan 20, 2023

The c.1322C>T (p.T441I) alteration is located in exon 4 (coding exon 4) of the SFPQ gene. This alteration results from a C to T substitution at nucleotide position 1322, causing the threonine (T) at amino acid position 441 to be replaced by an isoleucine (I). 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	0.94
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0065	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.40
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.51		Loss of glycosylation at T441 (P = 0.0061);
MVP		0.57
MPC		1.4
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.76

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: chr1-35656192;