17-76737017-G-C

Variant names:

• chr17-76737017-G-C
• rs237057
• NM_001195427.2:c.144C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001195427.2(SRSF2):​c.144C>G​(p.Asp48Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D48D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: SRSF2 NM_001195427.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• Publications: 30 publications found

Genes affected

SRSF2 (HGNC:10783): (serine and arginine rich splicing factor 2) The protein encoded by this gene is a member of the serine/arginine (SR)-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. Each of these factors contains an RNA recognition motif (RRM) for binding RNA and an RS domain for binding other proteins. The RS domain is rich in serine and arginine residues and facilitates interaction between different SR splicing factors. In addition to being critical for mRNA splicing, the SR proteins have also been shown to be involved in mRNA export from the nucleus and in translation. Two transcript variants encoding the same protein and one non-coding transcript variant have been found for this gene. In addition, a pseudogene of this gene has been found on chromosome 11. [provided by RefSeq, Sep 2010]

MFSD11 (HGNC:25458): (major facilitator superfamily domain containing 11) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267168 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.7085 (below the threshold of 3.09). Trascript score misZ: 3.8222 (above the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRSF2	NM_001195427.2	c.144C>G	p.Asp48Glu	missense_variant	Exon 1 of 3	ENST00000359995.10	NP_001182356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRSF2	ENST00000359995.10	c.144C>G	p.Asp48Glu	missense_variant	Exon 1 of 3	1	NM_001195427.2	ENSP00000353089.5
ENSG00000267168	ENST00000587459.1	c.239-1265G>C		intron_variant	Intron 1 of 1	5		ENSP00000466829.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 85

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 84309

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T;T;.;.;T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.0071
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	.;.;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.038	D
MutationAssessor	Uncertain	2.0	M;M;M;.;.
PhyloP100		2.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.0	D;D;.;.;.
REVEL	Pathogenic	0.65
Sift	Benign	0.077	T;T;.;.;.
Sift4G	Benign	0.076	T;T;T;T;.
Polyphen		0.28	B;B;.;.;.
Vest4		0.78
MutPred		0.92		Loss of phosphorylation at Y50 (P = 0.111);Loss of phosphorylation at Y50 (P = 0.111);Loss of phosphorylation at Y50 (P = 0.111);Loss of phosphorylation at Y50 (P = 0.111);Loss of phosphorylation at Y50 (P = 0.111);
MVP		0.75
MPC		1.9
ClinPred		0.93	D
GERP RS		1.3
PromoterAI		-0.021	Neutral
Varity_R		0.68
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

Other links and lift over

dbSNP: rs237057; hg19: chr17-74733099;