NM_020717.5:c.2192A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020717.5(SHROOM4):c.2192A>G(p.Glu731Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,210,477 control chromosomes in the GnomAD database, including 6 homozygotes. There are 883 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 6 hom., 74 hem., cov: 23)

Exomes 𝑓: 0.0023 ( 0 hom. 809 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.12

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

X-linked intellectual disability, Stocco dos Santos type
Inheritance: XL Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
complex neurodevelopmental disorder
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

SHROOM4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013019592).

BP6

Variant X-50633881-T-C is Benign according to our data. Variant chrX-50633881-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020717.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHROOM4	NM_020717.5	MANE Select	c.2192A>G	p.Glu731Gly	missense	Exon 4 of 9	NP_065768.2
SHROOM4	NR_027121.3		n.2368A>G		non_coding_transcript_exon	Exon 4 of 10
SHROOM4	NR_172068.1		n.2233A>G		non_coding_transcript_exon	Exon 3 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.2192A>G	p.Glu731Gly	missense	Exon 4 of 9	ENSP00000365188.2
SHROOM4	ENST00000289292.11	TSL:1	c.2192A>G	p.Glu731Gly	missense	Exon 4 of 10	ENSP00000289292.7
SHROOM4	ENST00000898514.1		c.2057A>G	p.Glu686Gly	missense	Exon 3 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

245

AN:

112316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000421

Gnomad AMI

AF:

0.0791

Gnomad AMR

AF:

0.000281

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00258

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00293

Gnomad OTH

AF:

0.00197

GnomAD2 exomes

AF:

0.00136

AC:

249

AN:

183079

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00331

Gnomad NFE exome

AF:

0.00218

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00227

AC:

2490

AN:

1098161

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

809

AN XY:

363515

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

26400

American (AMR)

AF:

0.000256

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54124

European-Finnish (FIN)

AF:

0.00284

AC:

115

AN:

40522

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00273

AC:

2300

AN:

842089

Other (OTH)

AF:

0.00119

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

133

266

400

533

666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00218

AC:

245

AN:

112316

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

AN XY:

34480

show subpopulations

African (AFR)

AF:

0.000421

AC:

AN:

30857

American (AMR)

AF:

0.000281

AC:

AN:

10674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3546

South Asian (SAS)

AF:

0.00

AC:

AN:

2705

European-Finnish (FIN)

AF:

0.00258

AC:

AN:

6195

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00293

AC:

156

AN:

53248

Other (OTH)

AF:

0.00197

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00213

Hom.:

114

Bravo

AF:

0.00223

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00588

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00238

AC:

ExAC

AF:

0.00101

AC:

122

EpiCase

AF:

0.00267

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

X-linked intellectual disability, Stocco dos Santos type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.0089

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.3

PhyloP100

2.1

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.4

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.45

MVP

0.98

MPC

0.57

ClinPred

0.034

GERP RS

5.7

Varity_R

0.63

gMVP

0.49

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over