rs189694750

chrX-50635637-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_020717.5(SHROOM4):c.436C>T(p.Arg146Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,206,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 93 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 11 hem., cov: 21)
  • Exomes 𝑓: 0.00019 (0 hom. 82 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.91

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058234334).
• BP6: Variant X-50635637-G-A is Benign according to our data. Variant chrX-50635637-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417739.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chrX-50635637-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5	c.436C>T	p.Arg146Trp	missense_variant	4/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9	c.436C>T	p.Arg146Trp	missense_variant	4/9	2	NM_020717.5	P1
SHROOM4	ENST00000289292.11	c.436C>T	p.Arg146Trp	missense_variant	4/10	1		P1
SHROOM4	ENST00000460112.3	c.88C>T	p.Arg30Trp	missense_variant	3/8	5

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 33 AN: 109439 Hom.: 0 Cov.: 21 AF XY: 0.000346 AC XY: 11 AN XY: 31747

Gnomad AFR AF: 0.0000334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00723

Gnomad SAS AF: 0.00127

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0000572

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000680 AC: 124 AN: 182456 Hom.: 1 AF XY: 0.000746 AC XY: 50 AN XY: 67020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00759

Gnomad SAS exome AF: 0.000372

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000982

Gnomad OTH exome AF: 0.000887

GnomAD4 exome AF: 0.000188 AC: 206 AN: 1097314 Hom.: 0 Cov.: 32 AF XY: 0.000226 AC XY: 82 AN XY: 362966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00424

Gnomad4 SAS exome AF: 0.000426

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000439

Gnomad4 OTH exome AF: 0.000261

GnomAD4 genome AF: 0.000301 AC: 33 AN: 109489 Hom.: 0 Cov.: 21 AF XY: 0.000346 AC XY: 11 AN XY: 31807

Gnomad4 AFR AF: 0.0000333

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00725

Gnomad4 SAS AF: 0.00127

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000572

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 3

Bravo AF: 0.000514

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked intellectual disability, Stocco dos Santos type Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Nov 15, 2022	- -

SHROOM4-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.062	T;T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.29
MVP		0.76
MPC		0.47
ClinPred		0.076	T
GERP RS		6.1
Varity_R		0.65
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs189694750; hg19: chrX-50378637; COSMIC: COSV99174102;