10-100924278-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018121.4(SLF2):c.1277T>C(p.Ile426Thr) 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. 13/20 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: 1.17

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05673656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLF2	NM_018121.4	c.1277T>C	p.Ile426Thr	missense_variant	5/20	ENST00000238961.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLF2	ENST00000238961.9	c.1277T>C	p.Ile426Thr	missense_variant	5/20	1	NM_018121.4	P2
SLF2	ENST00000370269.3	c.1277T>C	p.Ile426Thr	missense_variant	5/19	1		A2
SLF2	ENST00000370271.7	c.1277T>C	p.Ile426Thr	missense_variant	5/6	1
SLF2	ENST00000649226.1	c.1277T>C	p.Ile426Thr	missense_variant, NMD_transcript_variant	5/21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Sep 13, 2023

The c.1277T>C (p.I426T) alteration is located in exon 5 (coding exon 5) of the SLF2 gene. This alteration results from a T to C substitution at nucleotide position 1277, causing the isoleucine (I) at amino acid position 426 to be replaced by a threonine (T). 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	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.0058	T;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.033
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.52	T;T;T
Polyphen		0.13	B;P;.
Vest4		0.17
MutPred		0.24		Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);
MVP		0.42
MPC		0.20
ClinPred		0.24	T
GERP RS		3.7
Varity_R		0.073
gMVP		0.20

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: chr10-102684035;