rs151329289

chrX-50634398-C-T

Variant summary

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

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.0650

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=0.05225113).
• 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 GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5	c.1675G>A	p.Glu559Lys	missense_variant	4/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9	c.1675G>A	p.Glu559Lys	missense_variant	4/9	2	NM_020717.5	P1
SHROOM4	ENST00000289292.11	c.1675G>A	p.Glu559Lys	missense_variant	4/10	1		P1
SHROOM4	ENST00000460112.3	c.1327G>A	p.Glu443Lys	missense_variant	3/8	5

Frequencies

GnomAD3 genomes AF: 0.000386 AC: 43 AN: 111437 Hom.: 0 Cov.: 22 AF XY: 0.000268 AC XY: 9 AN XY: 33623

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: 57 AN: 180846 Hom.: 0 AF XY: 0.000244 AC XY: 16 AN XY: 65520

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.: 0 Cov.: 33 AF XY: 0.000559 AC XY: 203 AN XY: 363039

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: 43 AN: 111492 Hom.: 0 Cov.: 22 AF XY: 0.000267 AC XY: 9 AN XY: 33688

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.: 13

Bravo AF: 0.000348

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000329 AC: 40

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

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	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 29, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0070	T;T;.
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.78	T;.;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.92	D;D;N
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs151329289; hg19: chrX-50377398; COSMIC: COSV56797601;