NM_032290.4:c.737A>G

Variant names:

• chr5-94649596-A-G
• rs201153902
• NM_032290.4:c.737A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The NM_032290.4(SLF1):​c.737A>G​(p.Gln246Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,468,618 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/25 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (8 hom.)
• Consequence: SLF1 NM_032290.4 missense, splice_region
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.07
• Publications: 5 publications found

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 -5 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 5-94649596-A-G is Benign according to our data. Variant chr5-94649596-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2655591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032290.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLF1	NM_032290.4	MANE Select	c.737A>G	p.Gln246Arg	missense splice_region	Exon 6 of 21	NP_115666.2	Q9BQI6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLF1	ENST00000265140.10	TSL:2 MANE Select	c.737A>G	p.Gln246Arg	missense splice_region	Exon 6 of 21	ENSP00000265140.5	Q9BQI6-1
	SLF1	ENST00000908676.1		c.737A>G	p.Gln246Arg	missense splice_region	Exon 6 of 21	ENSP00000578735.1
	SLF1	ENST00000966410.1		c.737A>G	p.Gln246Arg	missense splice_region	Exon 6 of 21	ENSP00000636469.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00168 AC: 226 AN: 134766 AF XY: 0.00205

Gnomad AFR exome AF: 0.000138

Gnomad AMR exome AF: 0.000745

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.000208

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000614

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.000969 AC: 1275 AN: 1316292 Hom.: 8 Cov.: 30 AF XY: 0.00118 AC XY: 755 AN XY: 641958

African (AFR) AF: 0.000437 AC: 13 AN: 29730

American (AMR) AF: 0.000760 AC: 23 AN: 30266

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 30 AN: 22740

East Asian (EAS) AF: 0.0000290 AC: 1 AN: 34492

South Asian (SAS) AF: 0.00802 AC: 539 AN: 67228

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 46910

Middle Eastern (MID) AF: 0.00448 AC: 24 AN: 5356

European-Non Finnish (NFE) AF: 0.000567 AC: 582 AN: 1025868

Other (OTH) AF: 0.00115 AC: 62 AN: 53702

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74492

African (AFR) AF: 0.000144 AC: 6 AN: 41588

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00828 AC: 40 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000845 Hom.: 1

Bravo AF: 0.000533

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.00326 AC: 78

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.79	T
PhyloP100		3.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.13
Sift	Benign	0.070	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.035
MVP		0.64
MPC		0.074
ClinPred		0.011	T
GERP RS		4.6
Varity_R		0.082
gMVP		0.31
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.56		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201153902; hg19: chr5-93985301;