rs137923286

chrX-50598412-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020717.5(SHROOM4):c.4066G>A(p.Val1356Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,207,779 control chromosomes in the GnomAD database, including 5 homozygotes. There are 279 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., 36 hem., cov: 22)
  • Exomes 𝑓: 0.00081 (4 hom. 243 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.292

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037336648).
• BP6: Variant X-50598412-C-T is Benign according to our data. Variant chrX-50598412-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50598412-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000815 (893/1096138) while in subpopulation AMR AF= 0.0194 (680/34995). AF 95% confidence interval is 0.0182. There are 4 homozygotes in gnomad4_exome. There are 243 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5	c.4066G>A	p.Val1356Ile	missense_variant	8/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4066G>A	p.Val1356Ile	missense_variant	8/9	2	NM_020717.5	P1
SHROOM4	ENST00000289292.11	c.4066G>A	p.Val1356Ile	missense_variant	8/10	1		P1
SHROOM4	ENST00000460112.3	c.3718G>A	p.Val1240Ile	missense_variant	7/8	5

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 130 AN: 111589 Hom.: 1 Cov.: 22 AF XY: 0.00107 AC XY: 36 AN XY: 33767

Gnomad AFR AF: 0.000359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00944

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00337

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00266

GnomAD3 exomes AF: 0.00319 AC: 565 AN: 177184 Hom.: 1 AF XY: 0.00217 AC XY: 135 AN XY: 62098

Gnomad AFR exome AF: 0.000393

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00259

Gnomad SAS exome AF: 0.000277

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000254

Gnomad OTH exome AF: 0.00227

GnomAD4 exome AF: 0.000815 AC: 893 AN: 1096138 Hom.: 4 Cov.: 32 AF XY: 0.000672 AC XY: 243 AN XY: 361634

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.0194

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00465

Gnomad4 SAS exome AF: 0.000205

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.000826

GnomAD4 genome AF: 0.00116 AC: 129 AN: 111641 Hom.: 1 Cov.: 22 AF XY: 0.00106 AC XY: 36 AN XY: 33829

Gnomad4 AFR AF: 0.000358

Gnomad4 AMR AF: 0.00934

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00338

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000752

Gnomad4 OTH AF: 0.00263

Alfa AF: 0.000467 Hom.: 17

Bravo AF: 0.00189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00227 AC: 275

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 01, 2018	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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

SHROOM4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.4
Dann	Benign	0.69
DEOGEN2	Benign	0.0064	T;T;.
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.43	T;.;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Benign	0.010
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.015	B;B;.
Vest4		0.064
MVP		0.12
MPC		0.087
ClinPred		0.0038	T
GERP RS		0.65
Varity_R		0.042
gMVP		0.089

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137923286; hg19: chrX-50341412;