Genetic Variant SHROOM4:p.Ala1355Ala (chrX-50598413-G-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_020717.5(SHROOM4):c.4065C>A(p.Ala1355Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,207,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A1355A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 9 hem., cov: 22)

Exomes 𝑓: 0.000029 ( 0 hom. 9 hem. )

Consequence

SHROOM4
NM_020717.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.87

Publications

0 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant X-50598413-G-T is Benign according to our data. Variant chrX-50598413-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2660555.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-4.87 with no splicing effect.

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	UniProt
SHROOM4	NM_020717.5	MANE Select	c.4065C>A	p.Ala1355Ala	synonymous	Exon 8 of 9	NP_065768.2	Q9ULL8-1
SHROOM4	NR_027121.3		n.4241C>A		non_coding_transcript_exon	Exon 8 of 10
SHROOM4	NR_172068.1		n.4106C>A		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.4065C>A	p.Ala1355Ala	synonymous	Exon 8 of 9	ENSP00000365188.2	Q9ULL8-1
SHROOM4	ENST00000289292.11	TSL:1	c.4065C>A	p.Ala1355Ala	synonymous	Exon 8 of 10	ENSP00000289292.7	Q9ULL8-1
SHROOM4	ENST00000898514.1		c.3930C>A	p.Ala1310Ala	synonymous	Exon 7 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

111540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000620

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000381

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:

0.00

Gnomad OTH

AF:

0.00133

GnomAD2 exomes

AF:

0.0000960

AC:

AN:

177128

AF XY:

0.0000806

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.000111

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1096169

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

361653

show subpopulations

African (AFR)

AF:

0.000910

AC:

AN:

26373

American (AMR)

AF:

0.000171

AC:

AN:

35011

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19345

East Asian (EAS)

AF:

0.00

AC:

AN:

30140

South Asian (SAS)

AF:

0.00

AC:

AN:

53621

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40411

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841115

Other (OTH)

AF:

0.0000435

AC:

AN:

46020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000224

AC:

AN:

111593

Hom.:

Cov.:

AF XY:

0.000266

AC XY:

AN XY:

33785

show subpopulations

African (AFR)

AF:

0.000619

AC:

AN:

30693

American (AMR)

AF:

0.000381

AC:

AN:

10505

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2627

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53151

Other (OTH)

AF:

0.00131

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00

Hom.:

Bravo

AF:

0.000382

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.084

(source)

DANN

Benign

0.48

PhyloP100

-4.9

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over