4-76739578-C-G

Position:

chr4-76739578-C-G

Variant summary

Our verdict is Benign. Variant got -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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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=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 id 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/exons	MANE	Protein	UniProt
SHROOM3	NM_020859.4 linkuse as main transcript	c.1405C>G	p.Pro469Ala	missense_variant	5/11	ENST00000296043.7	NP_065910.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHROOM3	ENST00000296043.7 linkuse as main transcript	c.1405C>G	p.Pro469Ala	missense_variant	5/11	1	NM_020859.4	ENSP00000296043	P1	Q8TF72-1
SHROOM3-AS1	ENST00000666924.1 linkuse as main transcript	n.448+3230G>C		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.537

AC:

134921

AN:

251374

Hom.:

37685

AF XY:

0.539

AC XY:

73208

AN XY:

135870

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 SAS exome

AF:

0.447

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

Gnomad4 AFR exome

AF:

0.423

Gnomad4 AMR exome

AF:

0.508

Gnomad4 ASJ exome

AF:

0.648

Gnomad4 EAS exome

AF:

0.246

Gnomad4 SAS exome

AF:

0.448

Gnomad4 FIN exome

AF:

0.567

Gnomad4 NFE exome

AF:

0.616

Gnomad4 OTH exome

AF:

0.566

GnomAD4 genome

AF:

0.537

AC:

81589

AN:

152076

Hom.:

22639

Cov.:

AF XY:

0.530

AC XY:

39427

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.433

Gnomad4 AMR

AF:

0.535

Gnomad4 ASJ

AF:

0.643

Gnomad4 EAS

AF:

0.255

Gnomad4 SAS

AF:

0.433

Gnomad4 FIN

AF:

0.578

Gnomad4 NFE

AF:

0.613

Gnomad4 OTH

AF:

0.547

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

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

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;.

MutationTaster

Benign

0.0027

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

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