17-58005875-C-T

Position:

• chr17-58005875-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_006924.5(SRSF1):​c.478G>A​(p.Val160Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRSF1 NM_006924.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.83

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

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a chain Serine/arginine-rich splicing factor 1 (size 246) in uniprot entity SRSF1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_006924.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-58005875-C-T is Pathogenic according to our data. Variant chr17-58005875-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2429781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58005875-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRSF1	NM_006924.5	c.478G>A	p.Val160Met	missense_variant	3/4	ENST00000258962.5	NP_008855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRSF1	ENST00000258962.5	c.478G>A	p.Val160Met	missense_variant	3/4	1	NM_006924.5	ENSP00000258962.4
ENSG00000266086	ENST00000578794.2	n.478G>A		non_coding_transcript_exon_variant	3/6	3		ENSP00000463235.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Mar 19, 2024	This sequence variant is a single nucleotide substitution (G>A) at position 478 of the coding sequence of the SRSF1 gene that results in a valine to methionine amino acid change at residue 160 of the serine and arginine rich splicing factor 1 protein. The 160 residue falls in the RRM 2 domain (UniProt). This is a previously reported variant (ClinVar 2429781) that has been observed in individuals affected by a neurodevelopmental disorder (PMID: 37071997, 35468861). This variant is absent from the gnomAD population database v4.0.0 (0 of approximately 780,000 alleles). Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Val160 residue at this position is highly conserved across the vertebrate species examined. When introduced into Drosophilia, this variant disrupted serine and arginine rich splicing factor 1 protein's function (PMID: 37071997). Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PP2, PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 29, 2023	- -

Intellectual disability;C4022738:Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Feb 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	.;T;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Pathogenic	4.3	H;.;H
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	.;.;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	.;.;D
Sift4G	Uncertain	0.051	T;D;D
Polyphen		1.0	.;.;D
Vest4		0.56
MutPred		0.66		Loss of methylation at K165 (P = 0.1553);Loss of methylation at K165 (P = 0.1553);Loss of methylation at K165 (P = 0.1553);
MVP		0.71
MPC		3.1
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.96

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: chr17-56083236; COSMIC: COSV51966108; COSMIC: COSV51966108;