17-58007067-G-A

Variant names:

• chr17-58007067-G-A
• rs2143492189
• NM_006924.5:c.71C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_006924.5(SRSF1):​c.71C>T​(p.Pro24Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SRSF1 NM_006924.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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
• 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).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 17-58007067-G-A is Pathogenic according to our data. 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}. Variant chr17-58007067-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRSF1	NM_006924.5	c.71C>T	p.Pro24Leu	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.71C>T	p.Pro24Leu	missense_variant	Exon 1 of 4	1	NM_006924.5	ENSP00000258962.4
ENSG00000266086	ENST00000578794.2	n.71C>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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities Pathogenic:1

Aug 29, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Intellectual disability;C4022738:Neurodevelopmental delay Pathogenic:1

Feb 15, 2023

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Feb 01, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.091	.;T;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;.;.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-9.1	.;.;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.79
MutPred		0.64		Loss of phosphorylation at T29 (P = 0.1334);Loss of phosphorylation at T29 (P = 0.1334);Loss of phosphorylation at T29 (P = 0.1334);Loss of phosphorylation at T29 (P = 0.1334);
MVP		0.73
MPC		3.2
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.92
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs2143492189; hg19: chr17-56084428;