chrX-50607728-TTCC-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_020717.5(SHROOM4):c.3411_3413delGGA(p.Glu1138del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,111,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 64 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., 10 hem., cov: 14)

Exomes 𝑓: 0.00029 ( 0 hom. 54 hem. )

Consequence

SHROOM4
NM_020717.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.943

Publications

9 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 -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_020717.5

BP6

Variant X-50607728-TTCC-T is Benign according to our data. Variant chrX-50607728-TTCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 590248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.3411_3413delGGA	p.Glu1138del	disruptive_inframe_deletion	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.3411_3413delGGA	p.Glu1138del	disruptive_inframe_deletion	Exon 6 of 9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.3411_3413delGGA	p.Glu1138del	disruptive_inframe_deletion	Exon 6 of 10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.3063_3065delGGA	p.Glu1022del	disruptive_inframe_deletion	Exon 5 of 8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.000426

AC:

AN:

105667

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000388

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000605

Gnomad ASJ

AF:

0.00234

Gnomad EAS

AF:

0.00178

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00431

Gnomad NFE

AF:

0.000272

Gnomad OTH

AF:

0.000717

GnomAD2 exomes

AF:

0.000598

AC:

AN:

127114

AF XY:

0.000184

show subpopulations

Gnomad AFR exome

AF:

0.000335

Gnomad AMR exome

AF:

0.000547

Gnomad ASJ exome

AF:

0.00257

Gnomad EAS exome

AF:

0.00103

Gnomad FIN exome

AF:

0.000166

Gnomad NFE exome

AF:

0.000539

Gnomad OTH exome

AF:

0.000926

GnomAD4 exome

AF:

0.000285

AC:

287

AN:

1005455

Hom.:

AF XY:

0.000179

AC XY:

AN XY:

301399

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000413

AC:

AN:

24226

American (AMR)

AF:

0.000397

AC:

AN:

32777

Ashkenazi Jewish (ASJ)

AF:

0.00221

AC:

AN:

17680

East Asian (EAS)

AF:

0.000414

AC:

AN:

29002

South Asian (SAS)

AF:

0.000414

AC:

AN:

45849

European-Finnish (FIN)

AF:

0.000156

AC:

AN:

38470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3673

European-Non Finnish (NFE)

AF:

0.000228

AC:

176

AN:

771191

Other (OTH)

AF:

0.000282

AC:

AN:

42587

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.371

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000426

AC:

AN:

105703

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

AN XY:

28729

show subpopulations

African (AFR)

AF:

0.000387

AC:

AN:

28415

American (AMR)

AF:

0.000604

AC:

AN:

9934

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

2565

East Asian (EAS)

AF:

0.00179

AC:

AN:

3358

South Asian (SAS)

AF:

0.00

AC:

AN:

2256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5425

Middle Eastern (MID)

AF:

0.00474

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.000272

AC:

AN:

51470

Other (OTH)

AF:

0.000708

AC:

AN:

1412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

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:

0.00292

Hom.:

966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 10, 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. -

SHROOM4-related disorder

Benign:1

Mar 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SHROOM4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.94

Mutation Taster

=98/2

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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