rs142189648

Positions:

• chrX-50635342-T-C
• chrX-50635342-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020717.5(SHROOM4):​c.731A>G​(p.Asn244Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,200,910 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 103 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00031 (0 hom. 95 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.87

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068139136).
• BP6: Variant X-50635342-T-C is Benign according to our data. Variant chrX-50635342-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 212182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50635342-T-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5	c.731A>G	p.Asn244Ser	missense_variant	4/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9	c.731A>G	p.Asn244Ser	missense_variant	4/9	2	NM_020717.5	P1
SHROOM4	ENST00000289292.11	c.731A>G	p.Asn244Ser	missense_variant	4/10	1		P1
SHROOM4	ENST00000460112.3	c.383A>G	p.Asn128Ser	missense_variant	3/8	5

Frequencies

GnomAD3 genomes AF: 0.000259 AC: 29 AN: 111810 Hom.: 0 Cov.: 23 AF XY: 0.000235 AC XY: 8 AN XY: 34006

Gnomad AFR AF: 0.000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00313

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0000754

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000268 AC: 43 AN: 160256 Hom.: 0 AF XY: 0.000139 AC XY: 7 AN XY: 50276

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.000935

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000557

Gnomad SAS exome AF: 0.0000601

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000869

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000314 AC: 342 AN: 1089051 Hom.: 0 Cov.: 33 AF XY: 0.000267 AC XY: 95 AN XY: 356303

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000818

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00838

Gnomad4 SAS exome AF: 0.0000190

Gnomad4 FIN exome AF: 0.0000252

Gnomad4 NFE exome AF: 0.0000478

Gnomad4 OTH exome AF: 0.000306

GnomAD4 genome AF: 0.000259 AC: 29 AN: 111859 Hom.: 0 Cov.: 23 AF XY: 0.000235 AC XY: 8 AN XY: 34065

Gnomad4 AFR AF: 0.000259

Gnomad4 AMR AF: 0.000470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00313

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000754

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000253

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000190 AC: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 26, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2021	This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.96	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.0010
DANN	Benign	0.26
DEOGEN2	Benign	0.0020	T;T;.
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.20	T;.;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.060	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.14	N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.87	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.015
MVP		0.12
MPC		0.082
ClinPred		0.0036	T
GERP RS		-10
Varity_R		0.019
gMVP		0.074

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: rs142189648; hg19: chrX-50378342;