Genetic Variant SHROOM4:p.Glu1137_Glu1138dup (chrX-50607728-T-TTCCTCC) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_020717.5(SHROOM4):c.3408_3413dupGGAGGA(p.Glu1137_Glu1138dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,116,530 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. E1138dup) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000076 ( 0 hom., 3 hem., cov: 14)

Exomes 𝑓: 0.00013 ( 0 hom. 38 hem. )

Consequence

SHROOM4
NM_020717.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.350

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 -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_020717.5

BP6

Variant X-50607728-T-TTCCTCC is Benign according to our data. Variant chrX-50607728-T-TTCCTCC is described in ClinVar as Likely_benign. ClinVar VariationId is 3341614.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.3408_3413dupGGAGGA	p.Glu1137_Glu1138dup	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.3408_3413dupGGAGGA	p.Glu1137_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.3408_3413dupGGAGGA	p.Glu1137_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.3060_3065dupGGAGGA	p.Glu1021_Glu1022dup	disruptive_inframe_insertion	Exon 5 of 8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.0000757

AC:

AN:

105680

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000971

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000629

AC:

AN:

127114

AF XY:

0.0000306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000744

Gnomad OTH exome

AF:

0.000309

GnomAD4 exome

AF:

0.000135

AC:

136

AN:

1010850

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

304882

show subpopulations

African (AFR)

AF:

0.0000821

AC:

AN:

24358

American (AMR)

AF:

0.0000303

AC:

AN:

32962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17765

East Asian (EAS)

AF:

0.00

AC:

AN:

29101

South Asian (SAS)

AF:

0.000216

AC:

AN:

46306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38642

Middle Eastern (MID)

AF:

0.000815

AC:

AN:

3681

European-Non Finnish (NFE)

AF:

0.000147

AC:

114

AN:

775230

Other (OTH)

AF:

0.000140

AC:

AN:

42805

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

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:

0.0000757

AC:

AN:

105680

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

28688

show subpopulations

African (AFR)

AF:

0.000106

AC:

AN:

28362

American (AMR)

AF:

0.00

AC:

AN:

9925

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2565

East Asian (EAS)

AF:

0.00

AC:

AN:

3369

South Asian (SAS)

AF:

0.00

AC:

AN:

2263

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000971

AC:

AN:

51485

Other (OTH)

AF:

0.00

AC:

AN:

1396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000221

Hom.:

966

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

0.35

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-50607728-TTCCTCC-TTCCTCCTCCTCC

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