Genetic Variant SHROOM3:p.Gly279Ala (chr4-76739009-G-C) – ACMG Classification: Benign (-20 pts)

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.836G>C(p.Gly279Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,613,912 control chromosomes in the GnomAD database, including 440,353 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 (★★).

Frequency

Genomes: 𝑓 0.71 ( 38116 hom., cov: 33)

Exomes 𝑓: 0.74 ( 402237 hom. )

Consequence

SHROOM3
NM_020859.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.849

Publications

36 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=1.4019361E-6).

BP6

Variant 4-76739009-G-C is Benign according to our data. Variant chr4-76739009-G-C is described in ClinVar as Benign. ClinVar VariationId is 403437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHROOM3	NM_020859.4	MANE Select	c.836G>C	p.Gly279Ala	missense	Exon 5 of 11	NP_065910.3	Q8TF72-1
SHROOM3-AS1	NR_187404.1		n.1044+3799C>G		intron	N/A
SHROOM3-AS1	NR_187405.1		n.500+3799C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHROOM3	ENST00000296043.7	TSL:1 MANE Select	c.836G>C	p.Gly279Ala	missense	Exon 5 of 11	ENSP00000296043.6	Q8TF72-1
SHROOM3	ENST00000912766.1		c.839G>C	p.Gly280Ala	missense	Exon 5 of 11	ENSP00000582825.1
SHROOM3	ENST00000646790.1		c.593G>C	p.Gly198Ala	missense	Exon 4 of 10	ENSP00000494970.1	A0A2R8Y5P9

Frequencies

GnomAD3 genomes

AF:

0.705

AC:

107154

AN:

152010

Hom.:

38078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.630

Gnomad AMI

AF:

0.873

Gnomad AMR

AF:

0.722

Gnomad ASJ

AF:

0.747

Gnomad EAS

AF:

0.578

Gnomad SAS

AF:

0.724

Gnomad FIN

AF:

0.707

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.750

Gnomad OTH

AF:

0.706

GnomAD2 exomes

AF:

0.718

AC:

180327

AN:

251200

AF XY:

0.722

show subpopulations

Gnomad AFR exome

AF:

0.628

Gnomad AMR exome

AF:

0.710

Gnomad ASJ exome

AF:

0.751

Gnomad EAS exome

AF:

0.589

Gnomad FIN exome

AF:

0.700

Gnomad NFE exome

AF:

0.750

Gnomad OTH exome

AF:

0.720

GnomAD4 exome

AF:

0.740

AC:

1081391

AN:

1461784

Hom.:

402237

Cov.:

AF XY:

0.740

AC XY:

538349

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.626

AC:

20947

AN:

33480

American (AMR)

AF:

0.710

AC:

31751

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.749

AC:

19573

AN:

26136

East Asian (EAS)

AF:

0.512

AC:

20341

AN:

39694

South Asian (SAS)

AF:

0.733

AC:

63200

AN:

86252

European-Finnish (FIN)

AF:

0.698

AC:

37262

AN:

53412

Middle Eastern (MID)

AF:

0.675

AC:

3895

AN:

5768

European-Non Finnish (NFE)

AF:

0.756

AC:

840338

AN:

1111948

Other (OTH)

AF:

0.730

AC:

44084

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

19349

38698

58046

77395

96744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20322

40644

60966

81288

101610

<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:

0.705

AC:

107255

AN:

152128

Hom.:

38116

Cov.:

AF XY:

0.701

AC XY:

52158

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.631

AC:

26185

AN:

41498

American (AMR)

AF:

0.722

AC:

11044

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.747

AC:

2592

AN:

3470

East Asian (EAS)

AF:

0.578

AC:

2978

AN:

5156

South Asian (SAS)

AF:

0.724

AC:

3490

AN:

4822

European-Finnish (FIN)

AF:

0.707

AC:

7479

AN:

10582

Middle Eastern (MID)

AF:

0.765

AC:

225

AN:

294

European-Non Finnish (NFE)

AF:

0.750

AC:

50972

AN:

67988

Other (OTH)

AF:

0.707

AC:

1494

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1594

3188

4783

6377

7971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.742

Hom.:

31579

Bravo

AF:

0.706

TwinsUK

AF:

0.755

AC:

2799

ALSPAC

AF:

0.754

AC:

2905

ESP6500AA

AF:

0.629

AC:

2771

ESP6500EA

AF:

0.751

AC:

6462

ExAC

AF:

0.716

AC:

86891

Asia WGS

AF:

0.677

AC:

2353

AN:

3478

EpiCase

AF:

0.761

EpiControl

AF:

0.751

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

SHROOM3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.53

(source)

DANN

Benign

0.10

DEOGEN2

Benign

0.036

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0000014

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

PhyloP100

0.85

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.81

REVEL

Benign

0.18

Sift

Benign

0.70

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.010

MPC

0.34

ClinPred

0.010

GERP RS

-0.95

Varity_R

0.029

gMVP

0.076

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over