Genetic Variant SHROOM4:p.Glu1136_Glu1138dup (chrX-50607728-T-TTCCTCCTCC) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_020717.5(SHROOM4):c.3405_3413dupGGAGGAGGA(p.Glu1136_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 0.00000396 in 1,011,016 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1138dup) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 14)

Exomes 𝑓: 0.0000040 ( 0 hom. 1 hem. )

Consequence

SHROOM4
NM_020717.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.350

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_020717.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.3405_3413dupGGAGGAGGA	p.Glu1136_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.3405_3413dupGGAGGAGGA	p.Glu1136_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.3405_3413dupGGAGGAGGA	p.Glu1136_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.3057_3065dupGGAGGAGGA	p.Glu1020_Glu1022dup	disruptive_inframe_insertion	Exon 5 of 8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000396

AC:

AN:

1011016

Hom.:

Cov.:

AF XY:

0.00000328

AC XY:

AN XY:

304960

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

24363

American (AMR)

AF:

0.00

AC:

AN:

32962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17765

East Asian (EAS)

AF:

0.000103

AC:

AN:

29101

South Asian (SAS)

AF:

0.00

AC:

AN:

46315

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38642

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

775375

Other (OTH)

AF:

0.0000234

AC:

AN:

42811

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136242), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.35

Splicing

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

Publications

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X-50607728-TTCCTCC-TTCCTCCTCCTCCTCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over