NM_020717.5:c.3372_3383dupACAGCAGCAGCA

Variant names:

• chrX-50607758-C-CTGCTGCTGCTGT
• rs201922875
• NM_020717.5:c.3372_3383dupACAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_020717.5(SHROOM4):​c.3372_3383dupACAGCAGCAGCA​(p.Gln1125_Gln1128dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. 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. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1128Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.37 (6130 hom., 9764 hem., cov: 0)
  • Exomes 𝑓: 0.35 (46031 hom. 125882 hem.)
  • Failed GnomAD Quality Control
• Consequence: SHROOM4 NM_020717.5 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.676
• Publications: 11 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):

• 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_020717.5
• BP6: Variant X-50607758-C-CTGCTGCTGCTGT is Benign according to our data. Variant chrX-50607758-C-CTGCTGCTGCTGT is described in ClinVar as Benign. ClinVar VariationId is 95970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	NM_020717.5	MANE Select	c.3372_3383dupACAGCAGCAGCA	p.Gln1125_Gln1128dup	disruptive_inframe_insertion	Exon 6 of 9	NP_065768.2
	SHROOM4	NR_027121.3		n.3548_3559dupACAGCAGCAGCA		non_coding_transcript_exon	Exon 6 of 10
	SHROOM4	NR_172068.1		n.3413_3424dupACAGCAGCAGCA		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.3372_3383dupACAGCAGCAGCA	p.Gln1125_Gln1128dup	disruptive_inframe_insertion	Exon 6 of 9	ENSP00000365188.2
	SHROOM4	ENST00000289292.11	TSL:1	c.3372_3383dupACAGCAGCAGCA	p.Gln1125_Gln1128dup	disruptive_inframe_insertion	Exon 6 of 10	ENSP00000289292.7
	SHROOM4	ENST00000460112.3	TSL:5	c.3024_3035dupACAGCAGCAGCA	p.Gln1009_Gln1012dup	disruptive_inframe_insertion	Exon 5 of 8	ENSP00000421450.1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 39596 AN: 107497 Hom.: 6135 Cov.: 0

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.412

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.308 AC: 50914 AN: 165426 AF XY: 0.288

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.244

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.318

Gnomad OTH exome AF: 0.339

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.351 AC: 381596 AN: 1087767 Hom.: 46031 Cov.: 33 AF XY: 0.354 AC XY: 125882 AN XY: 355957

African (AFR) AF: 0.526 AC: 13767 AN: 26194

American (AMR) AF: 0.188 AC: 6568 AN: 34917

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 7577 AN: 19151

East Asian (EAS) AF: 0.256 AC: 7709 AN: 30108

South Asian (SAS) AF: 0.457 AC: 24380 AN: 53293

European-Finnish (FIN) AF: 0.273 AC: 10994 AN: 40203

Middle Eastern (MID) AF: 0.404 AC: 1637 AN: 4053

European-Non Finnish (NFE) AF: 0.350 AC: 292156 AN: 834145

Other (OTH) AF: 0.368 AC: 16808 AN: 45703

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.368 AC: 39606 AN: 107538 Hom.: 6130 Cov.: 0 AF XY: 0.323 AC XY: 9764 AN XY: 30272

African (AFR) AF: 0.499 AC: 14547 AN: 29142

American (AMR) AF: 0.266 AC: 2675 AN: 10069

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 977 AN: 2597

East Asian (EAS) AF: 0.235 AC: 801 AN: 3409

South Asian (SAS) AF: 0.386 AC: 901 AN: 2336

European-Finnish (FIN) AF: 0.217 AC: 1226 AN: 5640

Middle Eastern (MID) AF: 0.414 AC: 87 AN: 210

European-Non Finnish (NFE) AF: 0.340 AC: 17705 AN: 52034

Other (OTH) AF: 0.365 AC: 527 AN: 1443

Alfa AF: 0.358 Hom.: 3030

Asia WGS AF: 0.317 AC: 800 AN: 2522

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Aug 15, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 18, 2014

Genetic Services Laboratory, University of Chicago

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.68
Mutation Taster		=85/15	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs201922875; hg19: chrX-50350758; COSMIC: COSV56783736;