dbSNP rs148911180: SHROOM4:p.Arg89Lys (chrX-50695789-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020717.5(SHROOM4):c.266G>A(p.Arg89Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,210,207 control chromosomes in the GnomAD database, including 6 homozygotes. There are 755 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., 38 hem., cov: 23)

Exomes 𝑓: 0.0016 ( 5 hom. 717 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.57

Publications

3 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):

congenital anomaly of kidney and urinary tract
Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia
idiopathic generalized epilepsy
Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009545982).

BP6

Variant X-50695789-C-T is Benign according to our data. Variant chrX-50695789-C-T is described in ClinVar as Benign. ClinVar VariationId is 212178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00163 (1790/1098117) while in subpopulation MID AF = 0.0237 (98/4136). AF 95% confidence interval is 0.0199. There are 5 homozygotes in GnomAdExome4. There are 717 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 38 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	UniProt
SHROOM4	NM_020717.5	MANE Select	c.266G>A	p.Arg89Lys	missense	Exon 2 of 9	NP_065768.2	Q9ULL8-1
SHROOM4	NR_027121.3		n.442G>A		non_coding_transcript_exon	Exon 2 of 10
SHROOM4	NR_172068.1		n.442G>A		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.266G>A	p.Arg89Lys	missense	Exon 2 of 9	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11	TSL:1	c.266G>A	p.Arg89Lys	missense	Exon 2 of 10	ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000898514.1		c.266G>A	p.Arg89Lys	missense	Exon 2 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

136

AN:

112033

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.0106

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00463

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0130

Gnomad NFE

AF:

0.000977

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00213

AC:

391

AN:

183143

AF XY:

0.00256

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00156

Gnomad OTH exome

AF:

0.00464

GnomAD4 exome

AF:

0.00163

AC:

1790

AN:

1098117

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

717

AN XY:

363493

show subpopulations

African (AFR)

AF:

0.000417

AC:

AN:

26400

American (AMR)

AF:

0.00185

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

199

AN:

19385

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30203

South Asian (SAS)

AF:

0.00761

AC:

412

AN:

54145

European-Finnish (FIN)

AF:

0.0000740

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.0237

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00102

AC:

855

AN:

842028

Other (OTH)

AF:

0.00317

AC:

146

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00120

AC:

135

AN:

112090

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

34262

show subpopulations

African (AFR)

AF:

0.000292

AC:

AN:

30847

American (AMR)

AF:

0.00216

AC:

AN:

10632

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

AN:

2647

East Asian (EAS)

AF:

0.000282

AC:

AN:

3547

South Asian (SAS)

AF:

0.00465

AC:

AN:

2582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6189

Middle Eastern (MID)

AF:

0.00952

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.000977

AC:

AN:

53212

Other (OTH)

AF:

0.00520

AC:

AN:

1537

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00185

Hom.:

Bravo

AF:

0.00144

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00208

AC:

ExAC

AF:

0.00230

AC:

279

EpiCase

AF:

0.00256

EpiControl

AF:

0.00231

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0067

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

M_CAP

Benign

0.022

MetaRNN

Benign

0.0095

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

PhyloP100

4.6

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.33

REVEL

Benign

0.25

Sift

Benign

0.13

Sift4G

Benign

0.48

Polyphen

1.0

Vest4

0.13

MVP

0.19

MPC

0.42

ClinPred

0.025

GERP RS

5.2

Varity_R

0.13

gMVP

0.84

Mutation Taster

=51/49

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