17-58005923-C-T

Position:

• chr17-58005923-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006924.5(SRSF1):​c.430G>A​(p.Ala144Thr) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRSF1 NM_006924.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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 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	c.430G>A	p.Ala144Thr	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.430G>A	p.Ala144Thr	missense_variant	3/4	1	NM_006924.5	ENSP00000258962.4
ENSG00000266086	ENST00000578794.2	n.430G>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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2024

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Benign	0.95
DEOGEN2	Benign	0.028	.;T;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.9	.;.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	.;.;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.65
MutPred		0.78		Gain of phosphorylation at A144 (P = 0.0879);Gain of phosphorylation at A144 (P = 0.0879);Gain of phosphorylation at A144 (P = 0.0879);
MVP		0.53
MPC		3.1
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.89
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: chr17-56083284;