chr1-35192307-T-G

Position:

• chr1-35192307-T-G

Variant summary

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

The ENST00000357214.6(SFPQ):​c.743A>C​(p.His248Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SFPQ ENST00000357214.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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	Protein	UniProt
SFPQ	NM_005066.3	c.743A>C	p.His248Pro	missense_variant	1/10	ENST00000357214.6	NP_005057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFPQ	ENST00000357214.6	c.743A>C	p.His248Pro	missense_variant	1/10	1	NM_005066.3	ENSP00000349748	P1
SFPQ	ENST00000696553.1	c.806A>C	p.His269Pro	missense_variant	1/10			ENSP00000512713

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Jul 16, 2021

The c.743A>C (p.H248P) alteration is located in exon 1 (coding exon 1) of the SFPQ gene. This alteration results from a A to C substitution at nucleotide position 743, causing the histidine (H) at amino acid position 248 to be replaced by a proline (P). 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	0.074
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.93	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.16
Sift4G	Benign	0.43	T
Polyphen		0.94	P
Vest4		0.46
MutPred		0.28		Gain of glycosylation at H248 (P = 0.0122);
MVP		0.82
MPC		1.4
ClinPred		0.87	D
GERP RS		3.7
Varity_R		0.74
gMVP		0.27

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: chr1-35657908; COSMIC: COSV61758419; COSMIC: COSV61758419;