5-94695113-G-T

Variant names:

• chr5-94695113-G-T
• rs76504036
• NM_032290.4:c.2978G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032290.4(SLF1):​c.2978G>T​(p.Cys993Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLF1 NM_032290.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0360
• Publications: 8 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016307831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLF1	NM_032290.4	c.2978G>T	p.Cys993Phe	missense_variant	Exon 21 of 21	ENST00000265140.10	NP_115666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLF1	ENST00000265140.10	c.2978G>T	p.Cys993Phe	missense_variant	Exon 21 of 21	2	NM_032290.4	ENSP00000265140.5
SLF1	ENST00000450932.2	n.1560G>T		non_coding_transcript_exon_variant	Exon 7 of 7	1
SLF1	ENST00000493934.1	n.71+2857G>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151604 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0514 AC: 10399 AN: 202256 AF XY: 0.0523

Gnomad AFR exome AF: 0.0851

Gnomad AMR exome AF: 0.0626

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.0682

Gnomad FIN exome AF: 0.0799

Gnomad NFE exome AF: 0.0474

Gnomad OTH exome AF: 0.0263

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00708 AC: 10110 AN: 1428408 Hom.: 0 Cov.: 31 AF XY: 0.00803 AC XY: 5681 AN XY: 707644

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0122 AC: 395 AN: 32474

American (AMR) AF: 0.0588 AC: 2402 AN: 40820

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 458 AN: 24758

East Asian (EAS) AF: 0.0278 AC: 1056 AN: 37982

South Asian (SAS) AF: 0.0120 AC: 971 AN: 80882

European-Finnish (FIN) AF: 0.0214 AC: 1020 AN: 47700

Middle Eastern (MID) AF: 0.00414 AC: 23 AN: 5552

European-Non Finnish (NFE) AF: 0.00315 AC: 3466 AN: 1098914

Other (OTH) AF: 0.00538 AC: 319 AN: 59326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000264 AC: 4 AN: 151712 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74140

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67644

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000922 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.105 AC: 12701

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.036
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.026	D
Polyphen		0.068	B
Vest4		0.10
MPC		0.11
ClinPred		0.0010	T
GERP RS		2.6
Varity_R		0.24
gMVP		0.35
Mutation Taster		=94/6	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

Other links and lift over

dbSNP: rs76504036; hg19: chr5-94030818; COSMIC: COSV54367577; COSMIC: COSV54367577;