Variant X-50596895-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020717.5(SHROOM4):c.4282G>A(p.Val1428Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,210,061 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.000045 ( 0 hom. 17 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0840

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.065712065).

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM4	NM_020717.5 linkuse as main transcript	c.4282G>A	p.Val1428Met	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 linkuse as main transcript	c.4282G>A	p.Val1428Met	missense_variant	9/9	2	NM_020717.5	ENSP00000365188	P1	Q9ULL8-1
SHROOM4	ENST00000289292.11 linkuse as main transcript	c.4282G>A	p.Val1428Met	missense_variant	9/10	1		ENSP00000289292	P1	Q9ULL8-1
SHROOM4	ENST00000460112.3 linkuse as main transcript	c.3934G>A	p.Val1312Met	missense_variant	8/8	5		ENSP00000421450		Q9ULL8-2

Frequencies

GnomAD3 genomes

AF:

0.0000533

AC:

AN:

112482

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

34636

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000935

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:

0.0000938

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

180999

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

65635

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000372

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1097579

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

362959

show subpopulations

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:

0.0000546

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000533

AC:

AN:

112482

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

34636

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000935

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000938

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.4282G>A (p.V1428M) alteration is located in exon 9 (coding exon 9) of the SHROOM4 gene. This alteration results from a G to A substitution at nucleotide position 4282, causing the valine (V) at amino acid position 1428 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.011

T;T;.

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M;.

MutationTaster

Benign

0.95

D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.44

N;N;N

REVEL

Benign

0.044

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.80

P;P;.

Vest4

0.14

MutPred

0.43

Gain of disorder (P = 0.0648);Gain of disorder (P = 0.0648);.;

MVP

0.25

MPC

0.16

ClinPred

0.13

GERP RS

2.3

Varity_R

0.19

gMVP

0.29

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