17-58006514-C-T

Position:

• chr17-58006514-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_006924.5(SRSF1):​c.208G>A​(p.Ala70Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A70V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRSF1 NM_006924.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.12

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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
• PP5: Variant 17-58006514-C-T is Pathogenic according to our data. Variant chr17-58006514-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2429776.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-58006514-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRSF1	NM_006924.5	c.208G>A	p.Ala70Thr	missense_variant	2/4	ENST00000258962.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRSF1	ENST00000258962.5	c.208G>A	p.Ala70Thr	missense_variant	2/4	1	NM_006924.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	4.0	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	.;.;.;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.71
MutPred		0.66		Gain of phosphorylation at A70 (P = 0.0201);Gain of phosphorylation at A70 (P = 0.0201);Gain of phosphorylation at A70 (P = 0.0201);Gain of phosphorylation at A70 (P = 0.0201);
MVP		0.71
MPC		3.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.79
gMVP		0.98

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: chr17-56083875;