Genetic Variant SHROOM4:p.Glu1137_Glu1138del (chrX-50607728-TTCCTCC-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_020717.5(SHROOM4):c.3408_3413delGGAGGA(p.Glu1137_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 0.000156 in 1,116,663 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 50 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 4 hem., cov: 14)

Exomes 𝑓: 0.00016 ( 0 hom. 46 hem. )

Consequence

SHROOM4
NM_020717.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.08

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: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_020717.5

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.3408_3413delGGAGGA	p.Glu1137_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.3408_3413delGGAGGA	p.Glu1137_Glu1138del	disruptive_inframe_deletion	Exon 6 of 9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.3408_3413delGGAGGA	p.Glu1137_Glu1138del	disruptive_inframe_deletion	Exon 6 of 10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.3060_3065delGGAGGA	p.Glu1021_Glu1022del	disruptive_inframe_deletion	Exon 5 of 8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.000142

AC:

AN:

105682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000705

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000101

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000297

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000214

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000134

AC:

AN:

127114

AF XY:

0.0000919

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000829

Gnomad NFE exome

AF:

0.000279

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000157

AC:

159

AN:

1010981

Hom.:

AF XY:

0.000151

AC XY:

AN XY:

304927

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24363

American (AMR)

AF:

0.00

AC:

AN:

32961

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17764

East Asian (EAS)

AF:

0.00

AC:

AN:

29100

South Asian (SAS)

AF:

0.00

AC:

AN:

46314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3682

European-Non Finnish (NFE)

AF:

0.000195

AC:

151

AN:

775346

Other (OTH)

AF:

0.000187

AC:

AN:

42811

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000142

AC:

AN:

105682

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

28690

show subpopulations

African (AFR)

AF:

0.0000705

AC:

AN:

28362

American (AMR)

AF:

0.000101

AC:

AN:

9925

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2565

East Asian (EAS)

AF:

0.000297

AC:

AN:

3369

South Asian (SAS)

AF:

0.00

AC:

AN:

2263

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5427

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.000214

AC:

AN:

51486

Other (OTH)

AF:

0.00

AC:

AN:

1396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.00

Hom.:

966

Bravo

AF:

0.000136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=197/3

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over