chrX-50607728-T-TTCC

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. 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 (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant X-50607728-T-TTCC is Benign according to our data. Variant chrX-50607728-T-TTCC is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.3411_3413dupGGA	p.Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9	c.3411_3413dupGGA	p.Glu1138dup	disruptive_inframe_insertion	Exon 6 of 9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11	c.3411_3413dupGGA	p.Glu1138dup	disruptive_inframe_insertion	Exon 6 of 10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3	c.3063_3065dupGGA	p.Glu1022dup	disruptive_inframe_insertion	Exon 5 of 8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 28804 AN: 105509 Hom.: 3329 Cov.: 14 AF XY: 0.235 AC XY: 6729 AN XY: 28603

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

GnomAD3 exomes AF: 0.212 AC: 26912 AN: 127114 Hom.: 1812 AF XY: 0.103 AC XY: 3362 AN XY: 32658

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 SAS exome AF: 0.275

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

Gnomad4 AFR exome AF: 0.175

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.286

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

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.357

Gnomad4 FIN AF: 0.201

Gnomad4 NFE AF: 0.329

Gnomad4 OTH AF: 0.290

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 29, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 19, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Oct 11, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

X-linked intellectual disability, Stocco dos Santos type Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143151534; hg19: chrX-50350728;