5-94649525-C-G

Variant names:

• chr5-94649525-C-G
• NM_032290.4:c.666C>G

Variant summary

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

The NM_032290.4(SLF1):​c.666C>G​(p.Asn222Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,389,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.0000014 (0 hom.)
• Consequence: SLF1 NM_032290.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.463

Genes affected

SLF1 (HGNC:25408): (SMC5-SMC6 complex localization factor 1) 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 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=0.039507657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLF1	NM_032290.4	c.666C>G	p.Asn222Lys	missense_variant	Exon 6 of 21	ENST00000265140.10	NP_115666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLF1	ENST00000265140.10	c.666C>G	p.Asn222Lys	missense_variant	Exon 6 of 21	2	NM_032290.4	ENSP00000265140.5
SLF1	ENST00000508130.5	n.503C>G		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000424232.1
SLF1	ENST00000466957.1	n.360-12773C>G		intron_variant	Intron 3 of 5	5		ENSP00000430335.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1389872 Hom.: 0 Cov.: 30 AF XY: 0.00000292 AC XY: 2 AN XY: 685328

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: 0.00000187

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

not specified Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.666C>G (p.N222K) alteration is located in exon 6 (coding exon 5) of the SLF1 gene. This alteration results from a C to G substitution at nucleotide position 666, causing the asparagine (N) at amino acid position 222 to be replaced by a lysine (K). 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	0.082
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.68
DANN	Benign	0.82
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.11
Sift	Benign	0.32	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.13		Gain of ubiquitination at N222 (P = 0.0085);
MVP		0.19
MPC		0.078
ClinPred		0.078	T
GERP RS		1.9
Varity_R		0.086
gMVP		0.36

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: chr5-93985230;