4-76739578-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020859.4(SHROOM3):c.1405C>G(p.Pro469Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 1,613,930 control chromosomes in the GnomAD database, including 277,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 22639 hom., cov: 32)

Exomes 𝑓: 0.58 ( 255001 hom. )

Consequence

SHROOM3
NM_020859.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.33

Publications

34 publications found

Variant links:

Genes affected

SHROOM3 (HGNC:30422): (shroom family member 3) This gene encodes a PDZ-domain-containing protein that belongs to a family of Shroom-related proteins. This protein may be involved in regulating cell shape in certain tissues. A similar protein in mice is required for proper neurulation. [provided by RefSeq, Jan 2011]

SHROOM3 links:

SHROOM3-AS1 (HGNC:41265): (SHROOM3 antisense RNA 1)

SHROOM3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1504435E-5).

BP6

Variant 4-76739578-C-G is Benign according to our data. Variant chr4-76739578-C-G is described in ClinVar as Benign. ClinVar VariationId is 403439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM3	NM_020859.4 link	c.1405C>G	p.Pro469Ala	missense_variant	Exon 5 of 11	ENST00000296043.7	NP_065910.3	Q8TF72-1B3KY47
SHROOM3-AS1	NR_187404.1 link	n.1044+3230G>C		intron_variant	Intron 3 of 3
SHROOM3-AS1	NR_187405.1 link	n.500+3230G>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM3	ENST00000296043.7 link	c.1405C>G	p.Pro469Ala	missense_variant	Exon 5 of 11	1	NM_020859.4	ENSP00000296043.6		Q8TF72-1

Frequencies

GnomAD3 genomes

AF:

0.536

AC:

81511

AN:

151956

Hom.:

22615

Cov.:

show subpopulations

Gnomad AFR

AF:

0.432

Gnomad AMI

AF:

0.755

Gnomad AMR

AF:

0.535

Gnomad ASJ

AF:

0.643

Gnomad EAS

AF:

0.255

Gnomad SAS

AF:

0.434

Gnomad FIN

AF:

0.578

Gnomad MID

AF:

0.618

Gnomad NFE

AF:

0.613

Gnomad OTH

AF:

0.549

GnomAD2 exomes

AF:

0.537

AC:

134921

AN:

251374

AF XY:

0.539

show subpopulations

Gnomad AFR exome

AF:

0.432

Gnomad AMR exome

AF:

0.507

Gnomad ASJ exome

AF:

0.643

Gnomad EAS exome

AF:

0.256

Gnomad FIN exome

AF:

0.574

Gnomad NFE exome

AF:

0.612

Gnomad OTH exome

AF:

0.564

GnomAD4 exome

AF:

0.585

AC:

854693

AN:

1461854

Hom.:

255001

Cov.:

AF XY:

0.582

AC XY:

423230

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.423

AC:

14173

AN:

33480

American (AMR)

AF:

0.508

AC:

22720

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.648

AC:

16929

AN:

26136

East Asian (EAS)

AF:

0.246

AC:

9779

AN:

39700

South Asian (SAS)

AF:

0.448

AC:

38649

AN:

86258

European-Finnish (FIN)

AF:

0.567

AC:

30282

AN:

53408

Middle Eastern (MID)

AF:

0.543

AC:

3130

AN:

5768

European-Non Finnish (NFE)

AF:

0.616

AC:

684871

AN:

1111988

Other (OTH)

AF:

0.566

AC:

34160

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

24233

48466

72698

96931

121164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18194

36388

54582

72776

90970

<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:

0.537

AC:

81589

AN:

152076

Hom.:

22639

Cov.:

AF XY:

0.530

AC XY:

39427

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.433

AC:

17951

AN:

41488

American (AMR)

AF:

0.535

AC:

8181

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.643

AC:

2231

AN:

3468

East Asian (EAS)

AF:

0.255

AC:

1312

AN:

5150

South Asian (SAS)

AF:

0.433

AC:

2086

AN:

4816

European-Finnish (FIN)

AF:

0.578

AC:

6115

AN:

10580

Middle Eastern (MID)

AF:

0.630

AC:

184

AN:

292

European-Non Finnish (NFE)

AF:

0.613

AC:

41684

AN:

67968

Other (OTH)

AF:

0.547

AC:

1156

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1932

3863

5795

7726

9658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<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:

0.596

Hom.:

20588

Bravo

AF:

0.532

TwinsUK

AF:

0.618

AC:

2291

ALSPAC

AF:

0.613

AC:

2363

ESP6500AA

AF:

0.441

AC:

1943

ESP6500EA

AF:

0.614

AC:

5282

ExAC

AF:

0.534

AC:

64862

Asia WGS

AF:

0.354

AC:

1233

AN:

3478

EpiCase

AF:

0.629

EpiControl

AF:

0.621

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

SHROOM3-related disorder

Benign:1

Mar 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.000012

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

3.3

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.5

D;.

REVEL

Benign

0.12

Sift

Benign

0.049

D;.

Sift4G

Benign

0.27

T;.

Polyphen

0.67

P;.

Vest4

0.12

MPC

0.31

ClinPred

0.034

GERP RS

4.6

Varity_R

0.11

gMVP

0.33

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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