Genetic Variant SHROOM4:p.Glu1135_Glu1138dup (chrX-50607728-T-TTCCTCCTCCTCC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_020717.5(SHROOM4):c.3402_3413dupGGAGGAGGAGGA(p.Glu1135_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 0.000000989 in 1,011,020 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. 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: 9.9e-7 ( 0 hom. 0 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):

congenital anomaly of kidney and urinary tract
Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia
idiopathic generalized epilepsy
Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia
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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_020717.5

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020717.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHROOM4	NM_020717.5	MANE Select	c.3402_3413dupGGAGGAGGAGGA	p.Glu1135_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	NP_065768.2	Q9ULL8-1
SHROOM4	NR_027121.3		n.3578_3589dupGGAGGAGGAGGA		non_coding_transcript_exon	Exon 6 of 10
SHROOM4	NR_172068.1		n.3443_3454dupGGAGGAGGAGGA		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.3402_3413dupGGAGGAGGAGGA	p.Glu1135_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11	TSL:1	c.3402_3413dupGGAGGAGGAGGA	p.Glu1135_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 10	ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000898514.1		c.3267_3278dupGGAGGAGGAGGA	p.Glu1090_Glu1093dup	disruptive_inframe_insertion	Exon 5 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.89e-7

AC:

AN:

1011020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

304962

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:

0.00

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:

0.00000129

AC:

AN:

775379

Other (OTH)

AF:

0.00

AC:

AN:

42811

⚠️ 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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-TTCCTCCTCCTCCTCCTCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over