NM_020717.5:c.3372_3383dupACAGCAGCAGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_020717.5(SHROOM4):c.3372_3383dupACAGCAGCAGCA(p.Gln1125_Gln1128dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1128Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.37 ( 6130 hom., 9764 hem., cov: 0)

Exomes 𝑓: 0.35 ( 46031 hom. 125882 hem. )

Failed GnomAD Quality Control

Consequence

SHROOM4
NM_020717.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.676

Publications

11 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 -8 ACMG points.

BP6

Variant X-50607758-C-CTGCTGCTGCTGT is Benign according to our data. Variant chrX-50607758-C-CTGCTGCTGCTGT is described in ClinVar as [Benign]. Clinvar id is 95970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.3372_3383dupACAGCAGCAGCA	p.Gln1125_Gln1128dup	disruptive_inframe_insertion	Exon 6 of 9	ENST00000376020.9	NP_065768.2	Q9ULL8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHROOM4	ENST00000376020.9 link	c.3372_3383dupACAGCAGCAGCA	p.Gln1125_Gln1128dup	disruptive_inframe_insertion	Exon 6 of 9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.3372_3383dupACAGCAGCAGCA	p.Gln1125_Gln1128dup	disruptive_inframe_insertion	Exon 6 of 10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.3024_3035dupACAGCAGCAGCA	p.Gln1009_Gln1012dup	disruptive_inframe_insertion	Exon 5 of 8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

39596

AN:

107497

Hom.:

6135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.499

Gnomad AMI

AF:

0.243

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.235

Gnomad SAS

AF:

0.388

Gnomad FIN

AF:

0.217

Gnomad MID

AF:

0.412

Gnomad NFE

AF:

0.340

Gnomad OTH

AF:

0.369

GnomAD2 exomes

AF:

0.308

AC:

50914

AN:

165426

AF XY:

0.288

show subpopulations

Gnomad AFR exome

AF:

0.497

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.366

Gnomad EAS exome

AF:

0.244

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.318

Gnomad OTH exome

AF:

0.339

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.351

AC:

381596

AN:

1087767

Hom.:

46031

Cov.:

AF XY:

0.354

AC XY:

125882

AN XY:

355957

show subpopulations

African (AFR)

AF:

0.526

AC:

13767

AN:

26194

American (AMR)

AF:

0.188

AC:

6568

AN:

34917

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

7577

AN:

19151

East Asian (EAS)

AF:

0.256

AC:

7709

AN:

30108

South Asian (SAS)

AF:

0.457

AC:

24380

AN:

53293

European-Finnish (FIN)

AF:

0.273

AC:

10994

AN:

40203

Middle Eastern (MID)

AF:

0.404

AC:

1637

AN:

4053

European-Non Finnish (NFE)

AF:

0.350

AC:

292156

AN:

834145

Other (OTH)

AF:

0.368

AC:

16808

AN:

45703

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

7808

15615

23423

31230

39038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10132

20264

30396

40528

50660

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.368

AC:

39606

AN:

107538

Hom.:

6130

Cov.:

AF XY:

0.323

AC XY:

9764

AN XY:

30272

show subpopulations

African (AFR)

AF:

0.499

AC:

14547

AN:

29142

American (AMR)

AF:

0.266

AC:

2675

AN:

10069

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

977

AN:

2597

East Asian (EAS)

AF:

0.235

AC:

801

AN:

3409

South Asian (SAS)

AF:

0.386

AC:

901

AN:

2336

European-Finnish (FIN)

AF:

0.217

AC:

1226

AN:

5640

Middle Eastern (MID)

AF:

0.414

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.340

AC:

17705

AN:

52034

Other (OTH)

AF:

0.365

AC:

527

AN:

1443

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

853

1706

2560

3413

4266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.358

Hom.:

3030

Asia WGS

AF:

0.317

AC:

800

AN:

2522

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 15, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 19, 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. -

Apr 18, 2014

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked intellectual disability, Stocco dos Santos type

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.68

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

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