Genetic Variant RMI2:c.-516+6520C>A (chr16-11256298-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000572173.1(RMI2):c.-516+6520C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,236 control chromosomes in the GnomAD database, including 4,199 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.21 ( 4175 hom., cov: 32)

Exomes 𝑓: 0.28 ( 24 hom. )

Consequence

RMI2
ENST00000572173.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.341

Publications

20 publications found

Variant links:

Genes affected

RMI2 (HGNC:28349): (RecQ mediated genome instability 2) RMI2 is a component of the BLM (RECQL3; MIM 604610) complex, which plays a role in homologous recombination-dependent DNA repair and is essential for genome stability (Xu et al., 2008 [PubMed 18923082]).[supplied by OMIM, Nov 2008]

RMI2 links:

LOC105371082 (HGNC:):

LOC105371082 links:

SOCS1 (HGNC:19383): (suppressor of cytokine signaling 1) This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by a subset of cytokines, including IL2, IL3 erythropoietin (EPO), CSF2/GM-CSF, and interferon (IFN)-gamma. The protein encoded by this gene functions downstream of cytokine receptors, and takes part in a negative feedback loop to attenuate cytokine signaling. Knockout studies in mice suggested the role of this gene as a modulator of IFN-gamma action, which is required for normal postnatal growth and survival. [provided by RefSeq, Jul 2008]

SOCS1 Gene-Disease associations (from GenCC):

autoinflammatory syndrome with immunodeficiency
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autoimmune disease
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SOCS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC105371082	XR_933070.4 link	n.178+6520C>A		intron_variant	Intron 1 of 2
SOCS1	NM_003745.2 link	c.-270G>T		upstream_gene_variant		ENST00000332029.4	NP_003736.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOCS1	ENST00000332029.4 link	c.-270G>T		upstream_gene_variant		1	NM_003745.2	ENSP00000329418.2

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32206

AN:

151750

Hom.:

4177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0682

Gnomad AMI

AF:

0.460

Gnomad AMR

AF:

0.190

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.320

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.283

Gnomad OTH

AF:

0.236

GnomAD4 exome

AF:

0.278

AC:

104

AN:

374

Hom.:

AF XY:

0.293

AC XY:

AN XY:

270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.389

AC:

AN:

South Asian (SAS)

AF:

0.167

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.275

AC:

AN:

320

Other (OTH)

AF:

0.400

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.212

AC:

32185

AN:

151862

Hom.:

4175

Cov.:

AF XY:

0.211

AC XY:

15686

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.0680

AC:

2824

AN:

41518

American (AMR)

AF:

0.190

AC:

2906

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

757

AN:

3470

East Asian (EAS)

AF:

0.254

AC:

1296

AN:

5106

South Asian (SAS)

AF:

0.172

AC:

830

AN:

4824

European-Finnish (FIN)

AF:

0.320

AC:

3385

AN:

10562

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.283

AC:

19214

AN:

67790

Other (OTH)

AF:

0.233

AC:

491

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1229

2459

3688

4918

6147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

346

692

1038

1384

1730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.213

Hom.:

1532

Bravo

AF:

0.195

Asia WGS

AF:

0.192

AC:

664

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.6

(source)

DANN

Benign

0.82

PhyloP100

0.34

PromoterAI

-0.033

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over