rs151329289

Positions:

chrX-50634398-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020717.5(SHROOM4):c.1675G>A(p.Glu559Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,209,155 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 212 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.00053 ( 0 hom. 203 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.0650

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05225113).

BP6

Variant X-50634398-C-T is Benign according to our data. Variant chrX-50634398-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436721.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chrX-50634398-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM4	NM_020717.5 linkuse as main transcript	c.1675G>A	p.Glu559Lys	missense_variant	4/9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9 linkuse as main transcript	c.1675G>A	p.Glu559Lys	missense_variant	4/9	2	NM_020717.5	ENSP00000365188	P1	Q9ULL8-1
SHROOM4	ENST00000289292.11 linkuse as main transcript	c.1675G>A	p.Glu559Lys	missense_variant	4/10	1		ENSP00000289292	P1	Q9ULL8-1
SHROOM4	ENST00000460112.3 linkuse as main transcript	c.1327G>A	p.Glu443Lys	missense_variant	3/8	5		ENSP00000421450		Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.000386

AC:

AN:

111437

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

33623

show subpopulations

Gnomad AFR

AF:

0.0000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000716

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000315

AC:

AN:

180846

Hom.:

AF XY:

0.000244

AC XY:

AN XY:

65520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000734

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000107

Gnomad FIN exome

AF:

0.0000634

Gnomad NFE exome

AF:

0.000647

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000533

AC:

585

AN:

1097663

Hom.:

Cov.:

AF XY:

0.000559

AC XY:

203

AN XY:

363039

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.0000988

Gnomad4 NFE exome

AF:

0.000647

Gnomad4 OTH exome

AF:

0.000521

GnomAD4 genome

AF:

0.000386

AC:

AN:

111492

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

33688

show subpopulations

Gnomad4 AFR

AF:

0.0000652

Gnomad4 AMR

AF:

0.000285

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000716

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000531

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000329

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SHROOM4: BP4, BS2 -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 02, 2021	The c.1675G>A (p.E559K) alteration is located in exon 4 (coding exon 4) of the SHROOM4 gene. This alteration results from a G to A substitution at nucleotide position 1675, causing the glutamic acid (E) at amino acid position 559 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0070

T;T;.

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.78

T;.;T

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.

MutationTaster

Benign

0.92

D;D;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.48

N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0010

D;D;D

Sift4G

Benign

0.44

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.067

MVP

0.14

MPC

0.12

ClinPred

0.073

GERP RS

5.5

Varity_R

0.097

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over