X-50607728-TTCCTCC-TTCCTCCTCC

Variant names:

• chrX-50607728-T-TTCC
• rs143151534
• NM_020717.5:c.3411_3413dupGGA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_020717.5(SHROOM4):​c.3411_3413dupGGA​(p.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 0.282 in 1,091,571 control chromosomes in the GnomAD database, including 29,069 homozygotes. There are 71,921 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1138dup) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (3319 hom., 6730 hem., cov: 14)
  • Exomes 𝑓: 0.28 (25750 hom. 65191 hem.)
• Consequence: SHROOM4 NM_020717.5 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.350
• Publications: 9 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_020717.5
• BP6: Variant X-50607728-T-TTCC is Benign according to our data. Variant chrX-50607728-T-TTCC is described in ClinVar as Benign. ClinVar VariationId is 95971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

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.3411_3413dupGGA	p.Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	NP_065768.2	Q9ULL8-1
	SHROOM4	NR_027121.3		n.3587_3589dupGGA		non_coding_transcript_exon	Exon 6 of 10
	SHROOM4	NR_172068.1		n.3452_3454dupGGA		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.3411_3413dupGGA	p.Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	ENSP00000365188.2	Q9ULL8-1
	SHROOM4	ENST00000289292.11	TSL:1	c.3411_3413dupGGA	p.Glu1138dup	disruptive_inframe_insertion	Exon 6 of 10	ENSP00000289292.7	Q9ULL8-1
	SHROOM4	ENST00000898514.1		c.3276_3278dupGGA	p.Glu1093dup	disruptive_inframe_insertion	Exon 5 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 28804 AN: 105509 Hom.: 3329 Cov.: 14

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.353

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.212 AC: 26912 AN: 127114 AF XY: 0.103

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.283 AC: 278624 AN: 986025 Hom.: 25750 Cov.: 30 AF XY: 0.229 AC XY: 65191 AN XY: 284763

African (AFR) AF: 0.175 AC: 4208 AN: 24071

American (AMR) AF: 0.141 AC: 4600 AN: 32539

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 4937 AN: 17318

East Asian (EAS) AF: 0.224 AC: 6401 AN: 28615

South Asian (SAS) AF: 0.342 AC: 14903 AN: 43531

European-Finnish (FIN) AF: 0.238 AC: 9043 AN: 38021

Middle Eastern (MID) AF: 0.301 AC: 1076 AN: 3578

European-Non Finnish (NFE) AF: 0.293 AC: 221503 AN: 756492

Other (OTH) AF: 0.286 AC: 11953 AN: 41860

GnomAD4 genome AF: 0.273 AC: 28779 AN: 105546 Hom.: 3319 Cov.: 14 AF XY: 0.235 AC XY: 6730 AN XY: 28652

African (AFR) AF: 0.197 AC: 5577 AN: 28371

American (AMR) AF: 0.221 AC: 2189 AN: 9919

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 803 AN: 2563

East Asian (EAS) AF: 0.229 AC: 767 AN: 3347

South Asian (SAS) AF: 0.357 AC: 804 AN: 2250

European-Finnish (FIN) AF: 0.201 AC: 1087 AN: 5410

Middle Eastern (MID) AF: 0.360 AC: 76 AN: 211

European-Non Finnish (NFE) AF: 0.329 AC: 16906 AN: 51409

Other (OTH) AF: 0.290 AC: 409 AN: 1410

Alfa AF: 0.171 Hom.: 966

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	X-linked intellectual disability, Stocco dos Santos type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=84/16	polymorphism (auto)

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; COSMIC: COSV56786318;