X-50596874-C-A

Position:

• chrX-50596874-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020717.5(SHROOM4):​c.4303G>T​(p.Val1435Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,529 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.4303G>T	p.Val1435Leu	missense_variant	9/9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4303G>T	p.Val1435Leu	missense_variant	9/9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11	c.4303G>T	p.Val1435Leu	missense_variant	9/10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3	c.3955G>T	p.Val1319Leu	missense_variant	8/8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097529 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362905

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2017

The V1435L variant in the SHROOM4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1435L variant is not observed in large population cohorts (Lek et al., 2016). The V1435L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret V1435L as a variant of uncertain significance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.58
MutPred		0.73		Loss of ubiquitination at K1433 (P = 0.0962);Loss of ubiquitination at K1433 (P = 0.0962);.;
MVP		0.71
MPC		0.52
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.48
gMVP		0.52

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: rs1557246776; hg19: chrX-50339874;