22-30338890-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005877.6(SF3A1):c.1641del(p.Ser548AlafsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SF3A1 NM_005877.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.435

Genes affected

SF3A1 (HGNC:10765): (splicing factor 3a subunit 1) This gene encodes a subunit of the splicing factor 3a protein complex. The splicing factor 3a heterotrimer is a component of the mature U2 small nuclear ribonucleoprotein particle (snRNP). U2 small nuclear ribonucleoproteins play a critical role in spliceosome assembly and pre-mRNA splicing. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-30338890-TG-T is Pathogenic according to our data. Variant chr22-30338890-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 2671887.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SF3A1	NM_005877.6	c.1641del	p.Ser548AlafsTer66	frameshift_variant	11/16	ENST00000215793.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SF3A1	ENST00000215793.13	c.1641del	p.Ser548AlafsTer66	frameshift_variant	11/16	1	NM_005877.6	P1
SF3A1	ENST00000444440.1	c.594del	p.Ser199AlafsTer?	frameshift_variant	4/5	5
SF3A1	ENST00000485618.1	n.542del		non_coding_transcript_exon_variant	3/3	2
SF3A1	ENST00000411423.1	c.*140del		3_prime_UTR_variant, NMD_transcript_variant	3/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant lymphoma, large B-cell, diffuse Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Dec 04, 2023

Post-initial therapy specimen. This represents a frameshift deletion occuring in this splicosome factor at exon 11 of 12, predicted to cause loss of function. Alterations in SF3A1 function are predicted to be disease associated in multiple cancers, likely mediated through interference of the splicing of oncogenes/tumor suppressor transcripts (PMID 26498691). SF3A1 frameshift deletions have been reported in Gallbladder and Stomach carcinomas (PMID 22037554 and 33563892). -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-30734879;