rs757779263

Variant names:

• chr1-35192311-G-A
• rs757779263
• NM_005066.3:c.739C>T

Variant summary

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

The NM_005066.3(SFPQ):​c.739C>T​(p.His247Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000732 in 1,438,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: SFPQ NM_005066.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.85
• Publications: 0 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.1347667).
• BS2: High AC in GnomAd4 at 75 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005066.3. 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
	SFPQ	NM_005066.3	MANE Select	c.739C>T	p.His247Tyr	missense	Exon 1 of 10	NP_005057.1	P23246-1
	SFPQ	NR_136702.2		n.835C>T		non_coding_transcript_exon	Exon 1 of 12
	SFPQ	NR_136703.2		n.835C>T		non_coding_transcript_exon	Exon 1 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFPQ	ENST00000357214.6	TSL:1 MANE Select	c.739C>T	p.His247Tyr	missense	Exon 1 of 10	ENSP00000349748.5	P23246-1
	SFPQ	ENST00000696553.1		c.802C>T	p.His268Tyr	missense	Exon 1 of 10	ENSP00000512713.1	A0A8Q3WMA7

Frequencies

GnomAD3 genomes AF: 0.000494 AC: 75 AN: 151734 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000759

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000899

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000460 AC: 23 AN: 50024 AF XY: 0.000423

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: 0.000815

Gnomad NFE exome AF: 0.000673

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000760 AC: 978 AN: 1286530 Hom.: 0 Cov.: 33 AF XY: 0.000739 AC XY: 469 AN XY: 634504

African (AFR) AF: 0.000162 AC: 4 AN: 24696

American (AMR) AF: 0.00 AC: 0 AN: 16394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21520

East Asian (EAS) AF: 0.00 AC: 0 AN: 27458

South Asian (SAS) AF: 0.000411 AC: 28 AN: 68106

European-Finnish (FIN) AF: 0.00125 AC: 40 AN: 32044

Middle Eastern (MID) AF: 0.000263 AC: 1 AN: 3798

European-Non Finnish (NFE) AF: 0.000835 AC: 868 AN: 1039474

Other (OTH) AF: 0.000698 AC: 37 AN: 53040

GnomAD4 genome AF: 0.000494 AC: 75 AN: 151734 Hom.: 0 Cov.: 32 AF XY: 0.000378 AC XY: 28 AN XY: 74146

African (AFR) AF: 0.0000725 AC: 3 AN: 41360

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000759 AC: 8 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000899 AC: 61 AN: 67848

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.000635 Hom.: 0

Bravo AF: 0.000404

ExAC AF: 0.000324 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.064
Sift4G	Benign	0.46	T
Polyphen		0.66	P
Vest4		0.29
MVP		0.74
MPC		1.1
ClinPred		0.18	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.56
gMVP		0.19
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs757779263; hg19: chr1-35657912; COSMIC: COSV105257745;