Genetic Variant SFPQ:p.Gln253His (chr1-35192291-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005066.3(SFPQ):c.759G>T(p.Gln253His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

SFPQ
NM_005066.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00200

Variant links:

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]

SFPQ links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32629895).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFPQ	NM_005066.3 link	c.759G>T	p.Gln253His	missense_variant	Exon 1 of 10	ENST00000357214.6	NP_005057.1	P23246-1A0A384N5Z8Q86VG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFPQ	ENST00000357214.6 link	c.759G>T	p.Gln253His	missense_variant	Exon 1 of 10	1	NM_005066.3	ENSP00000349748.5		P23246-1
SFPQ	ENST00000696553.1 link	c.822G>T	p.Gln274His	missense_variant	Exon 1 of 10			ENSP00000512713.1		A0A8Q3WMA7

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151594

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000229

AC:

AN:

1309726

Hom.:

Cov.:

AF XY:

0.00000309

AC XY:

AN XY:

646520

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000129

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

AF:

0.0000330

AC:

AN:

151594

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74064

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.759G>T (p.Q253H) alteration is located in exon 1 (coding exon 1) of the SFPQ gene. This alteration results from a G to T substitution at nucleotide position 759, causing the glutamine (Q) at amino acid position 253 to be replaced by a histidine (H). 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

0.16

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

Eigen

Benign

0.094

Eigen_PC

Benign

0.059

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.3

REVEL

Benign

0.11

Sift4G

Benign

0.11

Polyphen

0.98

Vest4

0.42

MutPred

0.13

Loss of glycosylation at P249 (P = 0.1589);

MVP

0.89

MPC

0.89

ClinPred

0.50

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.23

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over