rs121434620

chrX-50607876-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020717.5(SHROOM4):c.3266C>T(p.Ser1089Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,418 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.0320

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1879808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM4	NM_020717.5	c.3266C>T	p.Ser1089Leu	missense_variant	6/9	ENST00000376020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM4	ENST00000376020.9	c.3266C>T	p.Ser1089Leu	missense_variant	6/9	2	NM_020717.5	P1
SHROOM4	ENST00000289292.11	c.3266C>T	p.Ser1089Leu	missense_variant	6/10	1		P1
SHROOM4	ENST00000460112.3	c.2918C>T	p.Ser973Leu	missense_variant	5/8	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000556 AC: 1 AN: 179989 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65895

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096418 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 361938

Gnomad4 AFR exome AF: 0.0000379

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked intellectual disability, Stocco dos Santos type Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	2.4
Dann	Benign	0.47
DEOGEN2	Benign	0.012	T;T;.
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.67	T;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	N;N;.
MutationTaster	Benign	2.7e-12	A;A;A
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.020
Sift	Benign	0.064	T;T;T
Sift4G	Benign	0.17	T;T;D
Polyphen		0.0	B;B;.
Vest4		0.029
MutPred		0.23		Loss of phosphorylation at S1089 (P = 0.0276);Loss of phosphorylation at S1089 (P = 0.0276);.;
MVP		0.043
MPC		0.091
ClinPred		0.012	T
GERP RS		0.83
Varity_R		0.052
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: rs121434620; hg19: chrX-50350876; COSMIC: COSV56795744;