rs760840999

Variant names:

• chr5-94643344-C-T
• rs760840999
• NM_032290.4:c.503C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032290.4(SLF1):​c.503C>T​(p.Ala168Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,544,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A168S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SLF1 NM_032290.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.924

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07213855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLF1	NM_032290.4	c.503C>T	p.Ala168Val	missense_variant	Exon 5 of 21	ENST00000265140.10	NP_115666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLF1	ENST00000265140.10	c.503C>T	p.Ala168Val	missense_variant	Exon 5 of 21	2	NM_032290.4	ENSP00000265140.5
SLF1	ENST00000466957.1	n.359+12601C>T		intron_variant	Intron 3 of 5	5		ENSP00000430335.1
SLF1	ENST00000508130.5	n.432-6110C>T		intron_variant	Intron 4 of 7	2		ENSP00000424232.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000654 AC: 10 AN: 152988 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000295 AC: 41 AN: 1392090 Hom.: 0 Cov.: 29 AF XY: 0.0000379 AC XY: 26 AN XY: 686548

African (AFR) AF: 0.00 AC: 0 AN: 31308

American (AMR) AF: 0.00 AC: 0 AN: 34698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24972

East Asian (EAS) AF: 0.00 AC: 0 AN: 35390

South Asian (SAS) AF: 0.000282 AC: 22 AN: 77952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49216

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5668

European-Non Finnish (NFE) AF: 0.0000140 AC: 15 AN: 1075188

Other (OTH) AF: 0.0000347 AC: 2 AN: 57698

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74218

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.000205 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.503C>T (p.A168V) alteration is located in exon 5 (coding exon 4) of the SLF1 gene. This alteration results from a C to T substitution at nucleotide position 503, causing the alanine (A) at amino acid position 168 to be replaced by a valine (V). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.92
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.038
Sift	Benign	0.22	T
Sift4G	Benign	1.0	T
Polyphen		0.43	B
Vest4		0.14
MutPred		0.32		Gain of sheet (P = 0.0085);
MVP		0.50
MPC		0.072
ClinPred		0.039	T
GERP RS		3.4
Varity_R		0.046
gMVP		0.34
Mutation Taster		=88/12	polymorphism

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

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Other links and lift over

dbSNP: rs760840999; hg19: chr5-93979049;