17-58007068-G-A

Variant names:

• chr17-58007068-G-A
• NM_006924.5:c.70C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_006924.5(SRSF1):​c.70C>T​(p.Pro24Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SRSF1 NM_006924.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.93

Genes affected

SRSF1 (HGNC:10780): (serine and arginine rich splicing factor 1) This gene encodes a member of the arginine/serine-rich splicing factor protein family. The encoded protein can either activate or repress splicing, depending on its phosphorylation state and its interaction partners. Multiple transcript variants have been found for this gene. There is a pseudogene of this gene on chromosome 13. [provided by RefSeq, Jun 2014]

ENSG00000266086 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a domain RRM 1 (size 75) in uniprot entity SRSF1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_006924.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-58007067-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1331676.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.9581 (above the threshold of 3.09). Trascript score misZ: 5.8555 (above the threshold of 3.09).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRSF1	NM_006924.5	c.70C>T	p.Pro24Ser	missense_variant	Exon 1 of 4	ENST00000258962.5	NP_008855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRSF1	ENST00000258962.5	c.70C>T	p.Pro24Ser	missense_variant	Exon 1 of 4	1	NM_006924.5	ENSP00000258962.4
ENSG00000266086	ENST00000578794.2	n.70C>T		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000463235.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Aug 02, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Autism spectrum disorder Uncertain:1

Aug 16, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	.;T;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.53	N;.;.;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.3	.;.;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Benign	0.094	T;T;T;T
Polyphen		1.0	.;.;.;D
Vest4		0.70
MutPred		0.60		Loss of catalytic residue at P24 (P = 0.0407);Loss of catalytic residue at P24 (P = 0.0407);Loss of catalytic residue at P24 (P = 0.0407);Loss of catalytic residue at P24 (P = 0.0407);
MVP		0.50
MPC		3.2
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.91
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-56084429;