14-69768856-T-C

Variant names:

• chr14-69768856-T-C
• rs750508395
• NM_001320214.2:c.256T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_001320214.2(SRSF5):​c.256T>C​(p.Ser86Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SRSF5 NM_001320214.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

Genes affected

SRSF5 (HGNC:10787): (serine and arginine rich splicing factor 5) 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity SRSF5_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.11340323).
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRSF5	NM_001320214.2	c.256T>C	p.Ser86Pro	missense_variant	Exon 4 of 8	ENST00000557154.6	NP_001307143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRSF5	ENST00000557154.6	c.256T>C	p.Ser86Pro	missense_variant	Exon 4 of 8	2	NM_001320214.2	ENSP00000451088.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000477 AC: 12 AN: 251492 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000178 AC: 26 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727242

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.000278 AC: 24 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 8.99e-7 AC: 1 AN: 1112004

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207297 AN: 0.000207297

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.256T>C (p.S86P) alteration is located in exon 4 (coding exon 3) of the SRSF5 gene. This alteration results from a T to C substitution at nucleotide position 256, causing the serine (S) at amino acid position 86 to be replaced by a proline (P). 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	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.045	T;T;T;.;T;.;T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	0.0086
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	.;.;T;.;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.83	L;L;.;.;L;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.15	T;T;T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T
Polyphen		0.0030	B;B;.;.;B;B;.;.
Vest4		0.34
MutPred		0.29		Loss of phosphorylation at S86 (P = 9e-04);Loss of phosphorylation at S86 (P = 9e-04);Loss of phosphorylation at S86 (P = 9e-04);Loss of phosphorylation at S86 (P = 9e-04);Loss of phosphorylation at S86 (P = 9e-04);.;Loss of phosphorylation at S86 (P = 9e-04);Loss of phosphorylation at S86 (P = 9e-04);
MVP		0.69
MPC		1.4
ClinPred		0.067	T
GERP RS		5.7
Varity_R		0.26
gMVP		0.50
Mutation Taster		=64/36	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

Publications

LitVar

Other links and lift over

dbSNP: rs750508395; hg19: chr14-70235573;