10-100916834-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018121.4(SLF2):c.449A>G(p.Tyr150Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,196 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (5 hom.)
• Consequence: SLF2 NM_018121.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0960

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003130436).
• BP6: Variant 10-100916834-A-G is Benign according to our data. Variant chr10-100916834-A-G is described in ClinVar as [Benign]. Clinvar id is 713982.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00652 (993/152344) while in subpopulation AFR AF= 0.023 (955/41582). AF 95% confidence interval is 0.0218. There are 16 homozygotes in gnomad4. There are 465 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLF2	NM_018121.4	c.449A>G	p.Tyr150Cys	missense_variant	3/20	ENST00000238961.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLF2	ENST00000238961.9	c.449A>G	p.Tyr150Cys	missense_variant	3/20	1	NM_018121.4	P2
SLF2	ENST00000370269.3	c.449A>G	p.Tyr150Cys	missense_variant	3/19	1		A2
SLF2	ENST00000370271.7	c.449A>G	p.Tyr150Cys	missense_variant	3/6	1
SLF2	ENST00000649226.1	c.449A>G	p.Tyr150Cys	missense_variant, NMD_transcript_variant	3/21

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 991 AN: 152226 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.00383

GnomAD3 exomes AF: 0.00173 AC: 434 AN: 251286 Hom.: 4 AF XY: 0.00126 AC XY: 171 AN XY: 135824

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000712 AC: 1041 AN: 1461852 Hom.: 5 Cov.: 31 AF XY: 0.000617 AC XY: 449 AN XY: 727222

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152344 Hom.: 16 Cov.: 32 AF XY: 0.00624 AC XY: 465 AN XY: 74504

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00170

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: 0.00379

Alfa AF: 0.00127 Hom.: 8

Bravo AF: 0.00740

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.061
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0030	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.70	T;T;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.67	N;D;N
REVEL	Benign	0.015
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.0010	B;D;.
Vest4		0.26
MVP		0.17
MPC		0.20
ClinPred		0.0029	T
GERP RS		-3.5
Varity_R		0.086
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs114300819; hg19: chr10-102676591; COSMIC: COSV99032392; COSMIC: COSV99032392;