rs28362302

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_020717.5(SHROOM4):c.4101G>T(p.Leu1367Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,209,098 control chromosomes in the GnomAD database, including 113 homozygotes. There are 1,771 hemizygotes in GnomAD. In-silico tool predicts 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 Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0065 ( 14 hom., 242 hem., cov: 23)

Exomes 𝑓: 0.0047 ( 99 hom. 1529 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.32

Publications

7 publications found

Variant links:

Genes affected

SHROOM4 (HGNC:29215): (shroom family member 4) This gene encodes a member of the APX/Shroom family, which contain an N-terminal PDZ domain and a C-terminal ASD2 motif. The encoded protein may play a role in cytoskeletal architecture. Mutations in this gene have been linked to the X-linked Stocco dos Santos syndrome characterized by cognitive disabilities. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2017]

SHROOM4 Gene-Disease associations (from GenCC):

X-linked intellectual disability, Stocco dos Santos type
Inheritance: XL Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
complex neurodevelopmental disorder
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

SHROOM4 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=0.004167825).

BP6

Variant X-50598377-C-A is Benign according to our data. Variant chrX-50598377-C-A is described in ClinVar as Benign. ClinVar VariationId is 95974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.4101G>T	p.Leu1367Phe	missense_variant	Exon 8 of 9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SHROOM4	ENST00000376020.9 link	c.4101G>T	p.Leu1367Phe	missense_variant	Exon 8 of 9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11 link	c.4101G>T	p.Leu1367Phe	missense_variant	Exon 8 of 10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3 link	c.3753G>T	p.Leu1251Phe	missense_variant	Exon 7 of 8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes

AF:

0.00648

AC:

722

AN:

111378

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000784

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0527

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00459

Gnomad FIN

AF:

0.000335

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.00866

GnomAD2 exomes

AF:

0.0139

AC:

2516

AN:

181444

AF XY:

0.00959

show subpopulations

Gnomad AFR exome

AF:

0.000997

Gnomad AMR exome

AF:

0.0817

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000629

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00891

GnomAD4 exome

AF:

0.00475

AC:

5209

AN:

1097671

Hom.:

Cov.:

AF XY:

0.00421

AC XY:

1529

AN XY:

363047

show subpopulations

African (AFR)

AF:

0.000455

AC:

AN:

26399

American (AMR)

AF:

0.0810

AC:

2843

AN:

35118

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.00380

AC:

205

AN:

53964

European-Finnish (FIN)

AF:

0.000173

AC:

AN:

40504

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00235

AC:

1976

AN:

841901

Other (OTH)

AF:

0.00356

AC:

164

AN:

46081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

237

474

710

947

1184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00647

AC:

721

AN:

111427

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

242

AN XY:

33605

show subpopulations

African (AFR)

AF:

0.000783

AC:

AN:

30668

American (AMR)

AF:

0.0526

AC:

548

AN:

10423

Ashkenazi Jewish (ASJ)

AF:

0.000378

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3546

South Asian (SAS)

AF:

0.00460

AC:

AN:

2609

European-Finnish (FIN)

AF:

0.000335

AC:

AN:

5977

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.00228

AC:

121

AN:

53139

Other (OTH)

AF:

0.00856

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00369

Hom.:

207

Bravo

AF:

0.0107

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00173

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00297

AC:

ExAC

AF:

0.00946

AC:

1148

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 13, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 16, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jul 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Apr 13, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.092

T;T;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;.;D

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.3

M;M;.

PhyloP100

1.3

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.039

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.27

MutPred

0.60

Gain of catalytic residue at L1367 (P = 0.0738);Gain of catalytic residue at L1367 (P = 0.0738);.;

MPC

0.55

ClinPred

0.018

GERP RS

3.5

Varity_R

0.32

gMVP

0.19

Mutation Taster

=93/7

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