rs28362302

chrX-50598377-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020717.5(SHROOM4):c.4101G>T(p.Leu1367Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,209,098 control chromosomes in the GnomAD database, including 113 homozygotes. There are 1,771 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (14 hom., 242 hem., cov: 23)
  • Exomes 𝑓: 0.0047 (99 hom. 1529 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.32

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=0.004167825).
• BP6: Variant X-50598377-C-A is Benign according to our data. Variant chrX-50598377-C-A is described in ClinVar as [Benign]. Clinvar id is 95974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50598377-C-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5	c.4101G>T	p.Leu1367Phe	missense_variant	8/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4101G>T	p.Leu1367Phe	missense_variant	8/9	2	NM_020717.5	P1
SHROOM4	ENST00000289292.11	c.4101G>T	p.Leu1367Phe	missense_variant	8/10	1		P1
SHROOM4	ENST00000460112.3	c.3753G>T	p.Leu1251Phe	missense_variant	7/8	5

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 722 AN: 111378 Hom.: 14 Cov.: 23 AF XY: 0.00721 AC XY: 242 AN XY: 33546

Gnomad AFR AF: 0.000784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0527

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00459

Gnomad FIN AF: 0.000335

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00866

GnomAD3 exomes AF: 0.0139 AC: 2516 AN: 181444 Hom.: 75 AF XY: 0.00959 AC XY: 633 AN XY: 66008

Gnomad AFR exome AF: 0.000997

Gnomad AMR exome AF: 0.0817

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00332

Gnomad FIN exome AF: 0.0000629

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00891

GnomAD4 exome AF: 0.00475 AC: 5209 AN: 1097671 Hom.: 99 Cov.: 32 AF XY: 0.00421 AC XY: 1529 AN XY: 363047

Gnomad4 AFR exome AF: 0.000455

Gnomad4 AMR exome AF: 0.0810

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00380

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.00235

Gnomad4 OTH exome AF: 0.00356

GnomAD4 genome AF: 0.00647 AC: 721 AN: 111427 Hom.: 14 Cov.: 23 AF XY: 0.00720 AC XY: 242 AN XY: 33605

Gnomad4 AFR AF: 0.000783

Gnomad4 AMR AF: 0.0526

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00460

Gnomad4 FIN AF: 0.000335

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00856

Alfa AF: 0.00246 Hom.: 101

Bravo AF: 0.0107

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00297 AC: 20

ExAC AF: 0.00946 AC: 1148

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 16, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 13, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;.;D
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	0.60	D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.039	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.27
MutPred		0.60		Gain of catalytic residue at L1367 (P = 0.0738);Gain of catalytic residue at L1367 (P = 0.0738);.;
MPC		0.55
ClinPred		0.018	T
GERP RS		3.5
Varity_R		0.32
gMVP		0.19

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: rs28362302; hg19: chrX-50341377;