chr5-94651768-A-G

Position:

• chr5-94651768-A-G

Variant summary

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

The NM_032290.4(SLF1):​c.805A>G​(p.Lys269Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,378,242 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: SLF1 NM_032290.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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 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=0.10772845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLF1	NM_032290.4	c.805A>G	p.Lys269Glu	missense_variant	7/21	ENST00000265140.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLF1	ENST00000265140.10	c.805A>G	p.Lys269Glu	missense_variant	7/21	2	NM_032290.4	P1
SLF1	ENST00000466957.1	c.361-10530A>G		intron_variant, NMD_transcript_variant		5
SLF1	ENST00000508130.5	c.*102A>G		3_prime_UTR_variant, NMD_transcript_variant	6/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000580 AC: 8 AN: 1378242 Hom.: 0 Cov.: 28 AF XY: 0.00000735 AC XY: 5 AN XY: 679820

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: 0.00000750

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.805A>G (p.K269E) alteration is located in exon 7 (coding exon 6) of the SLF1 gene. This alteration results from a A to G substitution at nucleotide position 805, causing the lysine (K) at amino acid position 269 to be replaced by a glutamic acid (E). 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	0.088
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.063
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.93	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.074
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.18	T
Polyphen		0.46	P
Vest4		0.098
MutPred		0.23		Loss of methylation at K269 (P = 0.004);
MVP		0.38
MPC		0.095
ClinPred		0.48	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1585151900; hg19: chr5-93987473;