4-76754352-C-T

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.3869C>T(p.Pro1290Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,613,826 control chromosomes in the GnomAD database, including 159,800 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1290P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.49 ( 18988 hom., cov: 32)

Exomes 𝑓: 0.43 ( 140812 hom. )

Consequence

SHROOM3
NM_020859.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.569

Publications

44 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=7.1187364E-6).

BP6

Variant 4-76754352-C-T is Benign according to our data. Variant chr4-76754352-C-T is described in ClinVar as Benign. ClinVar VariationId is 1280044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM3	NM_020859.4 link	c.3869C>T	p.Pro1290Leu	missense_variant	Exon 7 of 11	ENST00000296043.7	NP_065910.3	Q8TF72-1B3KY47
SHROOM3-AS1	NR_187404.1 link	n.951+3697G>A		intron_variant	Intron 2 of 3
SHROOM3-AS1	NR_187405.1 link	n.408-11452G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM3	ENST00000296043.7 link	c.3869C>T	p.Pro1290Leu	missense_variant	Exon 7 of 11	1	NM_020859.4	ENSP00000296043.6		Q8TF72-1

Frequencies

GnomAD3 genomes

AF:

0.488

AC:

74184

AN:

151870

Hom.:

18946

Cov.:

show subpopulations

Gnomad AFR

AF:

0.633

Gnomad AMI

AF:

0.450

Gnomad AMR

AF:

0.428

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.550

Gnomad SAS

AF:

0.510

Gnomad FIN

AF:

0.488

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.424

Gnomad OTH

AF:

0.430

GnomAD2 exomes

AF:

0.456

AC:

114354

AN:

251030

AF XY:

0.453

show subpopulations

Gnomad AFR exome

AF:

0.637

Gnomad AMR exome

AF:

0.438

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.559

Gnomad FIN exome

AF:

0.485

Gnomad NFE exome

AF:

0.419

Gnomad OTH exome

AF:

0.408

GnomAD4 exome

AF:

0.435

AC:

635759

AN:

1461838

Hom.:

140812

Cov.:

AF XY:

0.436

AC XY:

316919

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.637

AC:

21318

AN:

33478

American (AMR)

AF:

0.438

AC:

19566

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

6029

AN:

26134

East Asian (EAS)

AF:

0.496

AC:

19685

AN:

39700

South Asian (SAS)

AF:

0.511

AC:

44105

AN:

86252

European-Finnish (FIN)

AF:

0.485

AC:

25905

AN:

53414

Middle Eastern (MID)

AF:

0.277

AC:

1600

AN:

5768

European-Non Finnish (NFE)

AF:

0.424

AC:

471490

AN:

1111978

Other (OTH)

AF:

0.432

AC:

26061

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

22382

44764

67145

89527

111909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14572

29144

43716

58288

72860

<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:

0.489

AC:

74283

AN:

151988

Hom.:

18988

Cov.:

AF XY:

0.488

AC XY:

36277

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.633

AC:

26253

AN:

41446

American (AMR)

AF:

0.427

AC:

6534

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

818

AN:

3468

East Asian (EAS)

AF:

0.550

AC:

2833

AN:

5150

South Asian (SAS)

AF:

0.509

AC:

2449

AN:

4816

European-Finnish (FIN)

AF:

0.488

AC:

5154

AN:

10560

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.424

AC:

28838

AN:

67956

Other (OTH)

AF:

0.434

AC:

915

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1922

3843

5765

7686

9608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

666

1332

1998

2664

3330

<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:

0.432

Hom.:

51062

Bravo

AF:

0.487

TwinsUK

AF:

0.400

AC:

1485

ALSPAC

AF:

0.429

AC:

1654

ESP6500AA

AF:

0.618

AC:

2722

ESP6500EA

AF:

0.408

AC:

3505

ExAC

AF:

0.461

AC:

55921

Asia WGS

AF:

0.554

AC:

1926

AN:

3478

EpiCase

AF:

0.395

EpiControl

AF:

0.388

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.084

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.10

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.017

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.38

T;T

MetaRNN

Benign

0.0000071

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.7

N;.

PhyloP100

-0.57

PrimateAI

Benign

0.26

PROVEAN

Benign

1.5

N;.

REVEL

Benign

0.0050

Sift

Benign

0.23

T;.

Sift4G

Benign

0.52

T;.

Polyphen

0.0

B;.

Vest4

0.024

MPC

0.32

ClinPred

0.0028

GERP RS

-1.6

Varity_R

0.018

gMVP

0.071

Mutation Taster

=100/0

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