5-179837731-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_016175.4(MRNIP):c.692A>G(p.Gln231Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 1,614,018 control chromosomes in the GnomAD database, including 271,582 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.64 ( 32001 hom., cov: 34)

Exomes 𝑓: 0.57 ( 239581 hom. )

Consequence

MRNIP
NM_016175.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.98

Publications

76 publications found

Variant links:

Genes affected

MRNIP (HGNC:30817): (MRN complex interacting protein) Enables chromatin binding activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; regulation of double-strand break repair; and response to ionizing radiation. Located in nucleoplasm. Colocalizes with Mre11 complex. [provided by Alliance of Genome Resources, Apr 2022]

MRNIP links:

SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

SQSTM1 Gene-Disease associations (from GenCC):

neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
frontotemporal dementia and/or amyotrophic lateral sclerosis 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
osteosarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Paget disease of bone 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
behavioral variant of frontotemporal dementia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
frontotemporal dementia with motor neuron disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SQSTM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 5-179837731-T-C is Benign according to our data. Variant chr5-179837731-T-C is described in ClinVar as Benign. ClinVar VariationId is 353182.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRNIP	NM_016175.4 link	c.692A>G	p.Gln231Arg	missense_variant	Exon 7 of 7	ENST00000292586.11	NP_057259.2
SQSTM1	NM_003900.5 link	c.*1138T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000389805.9	NP_003891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRNIP	ENST00000292586.11 link	c.692A>G	p.Gln231Arg	missense_variant	Exon 7 of 7	1	NM_016175.4	ENSP00000292586.6
SQSTM1	ENST00000389805.9 link	c.*1138T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes

AF:

0.641

AC:

97429

AN:

152098

Hom.:

31963

Cov.:

show subpopulations

Gnomad AFR

AF:

0.764

Gnomad AMI

AF:

0.607

Gnomad AMR

AF:

0.710

Gnomad ASJ

AF:

0.627

Gnomad EAS

AF:

0.783

Gnomad SAS

AF:

0.634

Gnomad FIN

AF:

0.626

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.544

Gnomad OTH

AF:

0.619

GnomAD2 exomes

AF:

0.633

AC:

157771

AN:

249230

AF XY:

0.621

show subpopulations

Gnomad AFR exome

AF:

0.768

Gnomad AMR exome

AF:

0.800

Gnomad ASJ exome

AF:

0.631

Gnomad EAS exome

AF:

0.796

Gnomad FIN exome

AF:

0.622

Gnomad NFE exome

AF:

0.541

Gnomad OTH exome

AF:

0.610

GnomAD4 exome

AF:

0.568

AC:

829687

AN:

1461802

Hom.:

239581

Cov.:

AF XY:

0.568

AC XY:

413281

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.774

AC:

25911

AN:

33480

American (AMR)

AF:

0.787

AC:

35210

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.622

AC:

16258

AN:

26134

East Asian (EAS)

AF:

0.788

AC:

31297

AN:

39700

South Asian (SAS)

AF:

0.621

AC:

53550

AN:

86250

European-Finnish (FIN)

AF:

0.618

AC:

33009

AN:

53392

Middle Eastern (MID)

AF:

0.604

AC:

3480

AN:

5766

European-Non Finnish (NFE)

AF:

0.536

AC:

595519

AN:

1111962

Other (OTH)

AF:

0.587

AC:

35453

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

24159

48318

72478

96637

120796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17104

34208

51312

68416

85520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.641

AC:

97517

AN:

152216

Hom.:

32001

Cov.:

AF XY:

0.646

AC XY:

48049

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.764

AC:

31751

AN:

41542

American (AMR)

AF:

0.710

AC:

10866

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.627

AC:

2173

AN:

3468

East Asian (EAS)

AF:

0.783

AC:

4051

AN:

5174

South Asian (SAS)

AF:

0.632

AC:

3050

AN:

4826

European-Finnish (FIN)

AF:

0.626

AC:

6635

AN:

10596

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.543

AC:

36951

AN:

67992

Other (OTH)

AF:

0.621

AC:

1315

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1831

3663

5494

7326

9157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.576

Hom.:

119389

Bravo

AF:

0.653

TwinsUK

AF:

0.520

AC:

1930

ALSPAC

AF:

0.528

AC:

2033

ESP6500AA

AF:

0.766

AC:

3376

ESP6500EA

AF:

0.545

AC:

4685

ExAC

AF:

0.626

AC:

76018

Asia WGS

AF:

0.711

AC:

2473

AN:

3478

EpiCase

AF:

0.540

EpiControl

AF:

0.541

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Paget disease of bone 3

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0010

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.0065

.;T;T;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.014

MetaRNN

Benign

6.9e-7

T;T;T;T

MetaSVM

Benign

-0.98

PhyloP100

-5.0

PROVEAN

Benign

0.18

N;N;N;.

REVEL

Benign

0.027

Sift

Benign

1.0

T;T;T;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;.;B;.

Vest4

0.024

MPC

0.071

ClinPred

0.0085

GERP RS

-5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.025

gMVP

0.024

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: -14

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over