6-89098906-C-T

Variant names:

• chr6-89098906-C-T
• rs1018358315
• NM_080743.5:c.458G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080743.5(SRSF12):​c.458G>A​(p.Arg153His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,696 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SRSF12 NM_080743.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09267065).

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.458G>A	p.Arg153His	missense	Exon 5 of 5	NP_542781.3
	SRSF12	NM_001376896.1		c.173G>A	p.Arg58His	missense	Exon 5 of 5	NP_001363825.1
	SRSF12	NM_001376897.1		c.173G>A	p.Arg58His	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.458G>A	p.Arg153His	missense	Exon 5 of 5	ENSP00000414302.2	Q8WXF0
	SRSF12	ENST00000524221.1	TSL:2	n.740G>A		non_coding_transcript_exon	Exon 2 of 2
	SRSF12	ENST00000850585.1		n.*591G>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000520872.1	E5RJS0

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000479

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249024 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000547 AC: 8 AN: 1461682 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111856

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.0000656 AC: 1 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.075	T
Polyphen		0.0020	B
Vest4		0.24
MutPred		0.32		Gain of methylation at K155 (P = 0.1414)
MVP		0.23
MPC		1.4
ClinPred		0.88	D
GERP RS		4.0
Varity_R		0.13
gMVP		0.56
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1018358315; hg19: chr6-89808625;