NM_020717.5:c.1675G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020717.5(SHROOM4):c.1675G>A(p.Glu559Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,209,155 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 212 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.00053 ( 0 hom. 203 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.0650

Publications

4 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05225113).

BP6

Variant X-50634398-C-T is Benign according to our data. Variant chrX-50634398-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436721.

BS2

High Hemizygotes in GnomAd4 at 9 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.1675G>A	p.Glu559Lys	missense	Exon 4 of 9	NP_065768.2
SHROOM4	NR_027121.3		n.1851G>A		non_coding_transcript_exon	Exon 4 of 10
SHROOM4	NR_172068.1		n.1716G>A		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.1675G>A	p.Glu559Lys	missense	Exon 4 of 9	ENSP00000365188.2
SHROOM4	ENST00000289292.11	TSL:1	c.1675G>A	p.Glu559Lys	missense	Exon 4 of 10	ENSP00000289292.7
SHROOM4	ENST00000460112.3	TSL:5	c.1327G>A	p.Glu443Lys	missense	Exon 3 of 8	ENSP00000421450.1

Frequencies

GnomAD3 genomes

AF:

0.000386

AC:

AN:

111437

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

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:

0.000716

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000315

AC:

AN:

180846

AF XY:

0.000244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000734

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000634

Gnomad NFE exome

AF:

0.000647

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000533

AC:

585

AN:

1097663

Hom.:

Cov.:

AF XY:

0.000559

AC XY:

203

AN XY:

363039

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26396

American (AMR)

AF:

0.000199

AC:

AN:

35156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30179

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54024

European-Finnish (FIN)

AF:

0.0000988

AC:

AN:

40498

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000647

AC:

545

AN:

841828

Other (OTH)

AF:

0.000521

AC:

AN:

46074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000386

AC:

AN:

111492

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

33688

show subpopulations

African (AFR)

AF:

0.0000652

AC:

AN:

30676

American (AMR)

AF:

0.000285

AC:

AN:

10538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3511

South Asian (SAS)

AF:

0.00

AC:

AN:

2598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000716

AC:

AN:

53068

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000508

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000329

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SHROOM4: BP4, BS2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Uncertain:2

Aug 02, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1675G>A (p.E559K) alteration is located in exon 4 (coding exon 4) of the SHROOM4 gene. This alteration results from a G to A substitution at nucleotide position 1675, causing the glutamic acid (E) at amino acid position 559 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Jan 29, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0070

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

0.065

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.48

REVEL

Benign

0.14

Sift

Uncertain

0.0010

Sift4G

Benign

0.44

Polyphen

1.0

Vest4

0.067

MVP

0.14

MPC

0.12

ClinPred

0.073

GERP RS

5.5

Varity_R

0.097

gMVP

0.17

Mutation Taster

=98/2

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over