6-89098916-A-G

Variant names:

• chr6-89098916-A-G
• rs746010685
• NM_080743.5:c.448T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_080743.5(SRSF12):​c.448T>C​(p.Ser150Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SRSF12 NM_080743.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2771687).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080743.5. 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
	SRSF12	NM_080743.5	MANE Select	c.448T>C	p.Ser150Pro	missense	Exon 5 of 5	NP_542781.3
	SRSF12	NM_001376896.1		c.163T>C	p.Ser55Pro	missense	Exon 5 of 5	NP_001363825.1
	SRSF12	NM_001376897.1		c.163T>C	p.Ser55Pro	missense	Exon 5 of 5	NP_001363826.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRSF12	ENST00000452027.3	TSL:1 MANE Select	c.448T>C	p.Ser150Pro	missense	Exon 5 of 5	ENSP00000414302.2	Q8WXF0
	SRSF12	ENST00000524221.1	TSL:2	n.730T>C		non_coding_transcript_exon	Exon 2 of 2
	SRSF12	ENST00000850585.1		n.*581T>C		non_coding_transcript_exon	Exon 5 of 5	ENSP00000520872.1	E5RJS0

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000281 AC: 7 AN: 248986 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461632 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111830

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.000197 AC: 3 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.094
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.039	D
Polyphen		0.99	D
Vest4		0.32
MutPred		0.31		Loss of phosphorylation at S150 (P = 7e-04)
MVP		0.52
MPC		1.3
ClinPred		0.52	D
GERP RS		4.9
Varity_R		0.35
gMVP		0.53
Mutation Taster		=84/16	polymorphism

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: rs746010685; hg19: chr6-89808635;