10-100916786-C-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.401C>T(p.Pro134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,380 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SLF2 NM_018121.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.490

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=0.20256779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLF2	NM_018121.4	c.401C>T	p.Pro134Leu	missense_variant	3/20	ENST00000238961.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLF2	ENST00000238961.9	c.401C>T	p.Pro134Leu	missense_variant	3/20	1	NM_018121.4	P2
SLF2	ENST00000370269.3	c.401C>T	p.Pro134Leu	missense_variant	3/19	1		A2
SLF2	ENST00000370271.7	c.401C>T	p.Pro134Leu	missense_variant	3/6	1
SLF2	ENST00000649226.1	c.401C>T	p.Pro134Leu	missense_variant, NMD_transcript_variant	3/21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461380 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

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

Dec 19, 2022

The c.401C>T (p.P134L) alteration is located in exon 3 (coding exon 3) of the SLF2 gene. This alteration results from a C to T substitution at nucleotide position 401, causing the proline (P) at amino acid position 134 to be replaced by a leucine (L). 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	-0.065	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0014	T;T;.
Eigen	Benign	0.093
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.58	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.94	N;D;N
REVEL	Benign	0.18
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.43	T;D;T
Polyphen		1.0	D;D;.
Vest4		0.31
MutPred		0.41		Loss of catalytic residue at P134 (P = 0.0031);Loss of catalytic residue at P134 (P = 0.0031);Loss of catalytic residue at P134 (P = 0.0031);
MVP		0.37
MPC		0.16
ClinPred		0.79	D
GERP RS		4.6
Varity_R		0.074
gMVP		0.17

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: chr10-102676543;