X-50607728-TTCCTCC-TTCCTCCTCCTCCTCC

Variant names:

• chrX-50607728-T-TTCCTCCTCC
• rs143151534
• NM_020717.5:c.3405_3413dupGGAGGAGGA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.350
• Publications: 0 publications found

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

ACMG classification

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	NM_020717.5	MANE Select	c.3405_3413dupGGAGGAGGA	p.Glu1136_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	NP_065768.2	Q9ULL8-1
	SHROOM4	NR_027121.3		n.3581_3589dupGGAGGAGGA		non_coding_transcript_exon	Exon 6 of 10
	SHROOM4	NR_172068.1		n.3446_3454dupGGAGGAGGA		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.3405_3413dupGGAGGAGGA	p.Glu1136_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	ENSP00000365188.2	Q9ULL8-1
	SHROOM4	ENST00000289292.11	TSL:1	c.3405_3413dupGGAGGAGGA	p.Glu1136_Glu1138dup	disruptive_inframe_insertion	Exon 6 of 10	ENSP00000289292.7	Q9ULL8-1
	SHROOM4	ENST00000898514.1		c.3270_3278dupGGAGGAGGA	p.Glu1091_Glu1093dup	disruptive_inframe_insertion	Exon 5 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome AF: 0.00000396 AC: 4 AN: 1011016 Hom.: 0 Cov.: 30 AF XY: 0.00000328 AC XY: 1 AN XY: 304960

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

African (AFR) AF: 0.00 AC: 0 AN: 24363

American (AMR) AF: 0.00 AC: 0 AN: 32962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17765

East Asian (EAS) AF: 0.000103 AC: 3 AN: 29101

South Asian (SAS) AF: 0.00 AC: 0 AN: 46315

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 775375

Other (OTH) AF: 0.0000234 AC: 1 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.

GnomAD4 genome Cov.: 14

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

Other links and lift over

dbSNP: rs143151534; hg19: chrX-50350728;