10-100916819-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_018121.4(SLF2):c.434A>G(p.Lys145Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,614,118 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (4 hom.)
• Consequence: SLF2 NM_018121.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.969

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058882535).
• BP6: Variant 10-100916819-A-G is Benign according to our data. Variant chr10-100916819-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 713981.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLF2	NM_018121.4	c.434A>G	p.Lys145Arg	missense_variant	3/20	ENST00000238961.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLF2	ENST00000238961.9	c.434A>G	p.Lys145Arg	missense_variant	3/20	1	NM_018121.4	P2
SLF2	ENST00000370269.3	c.434A>G	p.Lys145Arg	missense_variant	3/19	1		A2
SLF2	ENST00000370271.7	c.434A>G	p.Lys145Arg	missense_variant	3/6	1
SLF2	ENST00000649226.1	c.434A>G	p.Lys145Arg	missense_variant, NMD_transcript_variant	3/21

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000705 AC: 177 AN: 251236 Hom.: 1 AF XY: 0.000552 AC XY: 75 AN XY: 135812

Gnomad AFR exome AF: 0.00899

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000281 AC: 411 AN: 1461776 Hom.: 4 Cov.: 31 AF XY: 0.000250 AC XY: 182 AN XY: 727204

Gnomad4 AFR exome AF: 0.00906

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00301 AC: 458 AN: 152342 Hom.: 2 Cov.: 32 AF XY: 0.00303 AC XY: 226 AN XY: 74502

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000518 Hom.: 2

Bravo AF: 0.00340

ESP6500AA AF: 0.00976 AC: 43

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.434A>G (p.K145R) alteration is located in exon 3 (coding exon 3) of the SLF2 gene. This alteration results from a A to G substitution at nucleotide position 434, causing the lysine (K) at amino acid position 145 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	16
Dann	Benign	0.80
DEOGEN2	Benign	0.0043	T;T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Benign	0.068
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.062	B;B;.
Vest4		0.20
MVP		0.21
MPC		0.17
ClinPred		0.013	T
GERP RS		1.7
Varity_R		0.029
gMVP		0.11

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: rs35608448; hg19: chr10-102676576; COSMIC: COSV99032383; COSMIC: COSV99032383;