Genetic Variant SRSF12:p.Gln201Arg (chr6-89098762-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080743.5(SRSF12):c.602A>G(p.Gln201Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

SRSF12
NM_080743.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Variant links:

Genes affected

SRSF12 (HGNC:21220): (serine and arginine rich splicing factor 12) Enables RNA binding activity. Involved in mRNA 5'-splice site recognition and regulation of alternative mRNA splicing, via spliceosome. Predicted to be located in nucleoplasm. Predicted to be active in cytoplasm and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

SRSF12 links:

PM20D2 (HGNC:21408): (peptidase M20 domain containing 2) Enables dipeptidase activity and identical protein binding activity. Acts upstream of or within proteolysis and regulation of cellular protein metabolic process. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PM20D2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.005839616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRSF12	NM_080743.5 link	c.602A>G	p.Gln201Arg	missense_variant	Exon 5 of 5	ENST00000452027.3	NP_542781.3	Q8WXF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SRSF12	ENST00000452027.3 link	c.602A>G	p.Gln201Arg	missense_variant	Exon 5 of 5	1	NM_080743.5	ENSP00000414302.2	Q8WXF0
SRSF12	ENST00000488604.1 link	n.*175A>G		downstream_gene_variant		2
SRSF12	ENST00000524221.1 link	n.*91A>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00288

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000193

AC:

AN:

249248

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

135218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00239

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000746

AC:

109

AN:

1461694

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00189

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000118

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ExAC

AF:

0.000166

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.602A>G (p.Q201R) alteration is located in exon 5 (coding exon 5) of the SRSF12 gene. This alteration results from a A to G substitution at nucleotide position 602, causing the glutamine (Q) at amino acid position 201 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.0065

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.61

M_CAP

Benign

0.0027

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.71

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.41

REVEL

Benign

0.10

Sift

Benign

0.15

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.14

MutPred

0.23

Gain of glycosylation at P200 (P = 0.0696);

MVP

0.20

MPC

0.89

ClinPred

0.054

GERP RS

5.2

Varity_R

0.039

gMVP

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over