NM_006924.5:c.119G>T

Variant names:

• chr17-58007019-C-A
• NM_006924.5:c.119G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_006924.5(SRSF1):​c.119G>T​(p.Gly40Val) variant causes a missense change. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SRSF1 NM_006924.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.06
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Baylor College of Medicine Research Center, PanelApp Australia

ENSG00000266086 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• 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). GenCC associations: The gene is linked to neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 17-58007019-C-A is Pathogenic according to our data. Variant chr17-58007019-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2429786.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006924.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRSF1	NM_006924.5	MANE Select	c.119G>T	p.Gly40Val	missense	Exon 1 of 4	NP_008855.1	Q07955-1
	SRSF1	NM_001078166.2		c.119G>T	p.Gly40Val	missense	Exon 1 of 3	NP_001071634.1	Q07955-3
	SRSF1	NR_034041.2		n.228G>T		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRSF1	ENST00000258962.5	TSL:1 MANE Select	c.119G>T	p.Gly40Val	missense	Exon 1 of 4	ENSP00000258962.4	Q07955-1
	ENSG00000266086	ENST00000578794.2	TSL:3	n.119G>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000463235.2
	SRSF1	ENST00000581979.5	TSL:1	n.119G>T		non_coding_transcript_exon	Exon 1 of 4	ENSP00000463223.1	Q07955-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability;C4022738:Neurodevelopmental delay (1)
1	-	-	Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.5	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.87		Loss of ubiquitination at K38 (P = 0.0714)
MVP		0.83
MPC		3.7
ClinPred		1.0	D
GERP RS		6.1
PromoterAI		-0.0048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		1.0

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

Other links and lift over

hg19: chr17-56084380;