4-76754352-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.456

AC:

114354

AN:

251030

Hom.:

27146

AF XY:

0.453

AC XY:

61532

AN XY:

135704

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 SAS exome

AF:

0.512

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

Gnomad4 AFR exome

AF:

0.637

Gnomad4 AMR exome

AF:

0.438

Gnomad4 ASJ exome

AF:

0.231

Gnomad4 EAS exome

AF:

0.496

Gnomad4 SAS exome

AF:

0.511

Gnomad4 FIN exome

AF:

0.485

Gnomad4 NFE exome

AF:

0.424

Gnomad4 OTH exome

AF:

0.432

GnomAD4 genome

AF:

0.489

AC:

74283

AN:

151988

Hom.:

18988

Cov.:

AF XY:

0.488

AC XY:

36277

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.633

Gnomad4 AMR

AF:

0.427

Gnomad4 ASJ

AF:

0.236

Gnomad4 EAS

AF:

0.550

Gnomad4 SAS

AF:

0.509

Gnomad4 FIN

AF:

0.488

Gnomad4 NFE

AF:

0.424

Gnomad4 OTH

AF:

0.434

Alfa

AF:

0.413

Hom.:

28144

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over