10-100917218-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018121.4(SLF2):c.833G>T(p.Ser278Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLF2 NM_018121.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.461

Genes affected

SLF2 (HGNC:17814): (SMC5-SMC6 complex localization factor 2) Enables ubiquitin protein ligase binding activity. Involved in several processes, including positive regulation of cellular component organization; positive regulation of double-strand break repair; and protein localization to site of double-strand break. Located in chromatin; nucleoplasm; and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106408894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLF2	NM_018121.4	c.833G>T	p.Ser278Ile	missense_variant	3/20	ENST00000238961.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLF2	ENST00000238961.9	c.833G>T	p.Ser278Ile	missense_variant	3/20	1	NM_018121.4	P2
SLF2	ENST00000370269.3	c.833G>T	p.Ser278Ile	missense_variant	3/19	1		A2
SLF2	ENST00000370271.7	c.833G>T	p.Ser278Ile	missense_variant	3/6	1
SLF2	ENST00000649226.1	c.833G>T	p.Ser278Ile	missense_variant, NMD_transcript_variant	3/21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.833G>T (p.S278I) alteration is located in exon 3 (coding exon 3) of the SLF2 gene. This alteration results from a G to T substitution at nucleotide position 833, causing the serine (S) at amino acid position 278 to be replaced by an isoleucine (I). 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	0.11
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0026	T;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.36	T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	N;D;N
REVEL	Benign	0.094
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.89	P;D;.
Vest4		0.19
MutPred		0.27		Loss of phosphorylation at S278 (P = 0.0018);Loss of phosphorylation at S278 (P = 0.0018);Loss of phosphorylation at S278 (P = 0.0018);
MVP		0.35
MPC		0.59
ClinPred		0.79	D
GERP RS		2.2
Varity_R		0.18
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr10-102676975;