Variant X-50596789-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_020717.5(SHROOM4):c.4388T>C(p.Ile1463Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,098,036 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.98

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5 link	c.4388T>C	p.Ile1463Thr	missense_variant	Exon 9 of 9	ENST00000376020.9	NP_065768.2	Q9ULL8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHROOM4	ENST00000376020.9 link	c.4388T>C	p.Ile1463Thr	missense_variant	Exon 9 of 9	2	NM_020717.5	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11 link	c.4388T>C	p.Ile1463Thr	missense_variant	Exon 9 of 10	1		ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000460112.3 link	c.4040T>C	p.Ile1347Thr	missense_variant	Exon 8 of 8	5		ENSP00000421450.1	Q9ULL8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

182988

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67474

show subpopulations

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:

0.0000527

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1098036

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363396

show subpopulations

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:

0.0000554

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked intellectual disability, Stocco dos Santos type

Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.4388T>C(p.Ile1463Thr) in SHROOM4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is reported with 0.001% allele frequency in gnomAD and is absent in 1000 Genomes. The amino acid Isoleucine at position 1463 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Ile1463Thr in SHROOM4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

T;T;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.016

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.61

MutPred

0.58

Gain of disorder (P = 0.0259);Gain of disorder (P = 0.0259);.;

MVP

0.34

MPC

0.59

ClinPred

0.82

GERP RS

4.8

Varity_R

0.58

gMVP

0.20

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