1-29148602-A-C

Variant names:

• chr1-29148602-A-C
• rs767598320
• NM_005626.5:c.1293T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005626.5(SRSF4):​c.1293T>G​(p.Ser431Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SRSF4 NM_005626.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.917
• Publications: 0 publications found

Genes affected

SRSF4 (HGNC:10786): (serine and arginine rich splicing factor 4) Enables RNA binding activity. Involved in negative regulation of mRNA splicing, via spliceosome. Located in nuclear speck. Biomarker of Down syndrome; acute myeloid leukemia; clear cell renal cell carcinoma; and colon adenocarcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000305828 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040955573).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005626.5. 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
	SRSF4	NM_005626.5	MANE Select	c.1293T>G	p.Ser431Arg	missense	Exon 6 of 6	NP_005617.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRSF4	ENST00000373795.7	TSL:1 MANE Select	c.1293T>G	p.Ser431Arg	missense	Exon 6 of 6	ENSP00000362900.4	Q08170
	SRSF4	ENST00000870274.1		c.1311T>G	p.Ser437Arg	missense	Exon 6 of 6	ENSP00000540333.1
	SRSF4	ENST00000969505.1		c.1287T>G	p.Ser429Arg	missense	Exon 6 of 6	ENSP00000639564.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461772 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.92
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.049
Sift	Uncertain	0.022	D
Sift4G	Benign	0.39	T
Polyphen		0.0030	B
Vest4		0.22
MutPred		0.30		Loss of phosphorylation at S431 (P = 0.0011)
MVP		0.27
MPC		0.25
ClinPred		0.20	T
GERP RS		0.20
Varity_R		0.063
gMVP		0.42
Mutation Taster		=85/15	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: rs767598320; hg19: chr1-29475114;