Variant 17-58007008-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_006924.5(SRSF1):c.130G>A(p.Asp44Asn) 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: 33)

Consequence

SRSF1
NM_006924.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.06

Variant links:

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]

SRSF1 links:

ENSG00000266086 (HGNC:):

ENSG00000266086 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRSF1	NM_006924.5 linkuse as main transcript	c.130G>A	p.Asp44Asn	missense_variant	1/4	ENST00000258962.5	NP_008855.1	Q07955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRSF1	ENST00000258962.5 linkuse as main transcript	c.130G>A	p.Asp44Asn	missense_variant	1/4	1	NM_006924.5	ENSP00000258962.4		Q07955-1
ENSG00000266086	ENST00000578794.2 linkuse as main transcript	n.130G>A		non_coding_transcript_exon_variant	1/6	3		ENSP00000463235.2		J3QKU1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability;C4022738:Neurodevelopmental delay

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Feb 15, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2023

De novo variant with confirmed parentage in a patient with neurodevelopmental features in the published literature (PMID: 37071997); Published functional studies indicate that this variant allows SRSF1 to retain splicing activity and may not lead to a loss of function (Bogaert et al., 2023); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37071997) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

.;T;.;T

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Benign

0.0059

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;.;M

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.1

.;.;.;N

REVEL

Benign

0.046

Sift

Benign

0.30

.;.;.;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.029

.;.;.;B

Vest4

0.73

MutPred

0.29

Gain of MoRF binding (P = 0.0653);Gain of MoRF binding (P = 0.0653);Gain of MoRF binding (P = 0.0653);Gain of MoRF binding (P = 0.0653);

MVP

0.37

MPC

1.8

ClinPred

0.96

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.83

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over