Genetic Variant NM_020717.5:c.3147G>A (chrX-50607995-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.3147G>A(p.Met1049Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,210,147 control chromosomes in the GnomAD database, including 33 homozygotes. There are 693 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 Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 18 hom., 322 hem., cov: 22)

Exomes 𝑓: 0.0013 ( 15 hom. 371 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.229

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026309788).

BP6

Variant X-50607995-C-T is Benign according to our data. Variant chrX-50607995-C-T is described in ClinVar as Benign. ClinVar VariationId is 235507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1206/111955) while in subpopulation AFR AF = 0.0368 (1134/30801). AF 95% confidence interval is 0.035. There are 18 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 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.3147G>A	p.Met1049Ile	missense	Exon 6 of 9	NP_065768.2
SHROOM4	NR_027121.3		n.3323G>A		non_coding_transcript_exon	Exon 6 of 10
SHROOM4	NR_172068.1		n.3188G>A		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.3147G>A	p.Met1049Ile	missense	Exon 6 of 9	ENSP00000365188.2
SHROOM4	ENST00000289292.11	TSL:1	c.3147G>A	p.Met1049Ile	missense	Exon 6 of 10	ENSP00000289292.7
SHROOM4	ENST00000898514.1		c.3012G>A	p.Met1004Ile	missense	Exon 5 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1185

AN:

111903

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00407

Gnomad ASJ

AF:

0.00264

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00322

AC:

588

AN:

182712

AF XY:

0.00172

show subpopulations

Gnomad AFR exome

AF:

0.0391

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00361

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000492

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.00129

AC:

1413

AN:

1098192

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

371

AN XY:

363546

show subpopulations

African (AFR)

AF:

0.0404

AC:

1067

AN:

26402

American (AMR)

AF:

0.00134

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.000296

AC:

AN:

54121

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.000967

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000344

AC:

AN:

842122

Other (OTH)

AF:

0.00336

AC:

155

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

146

218

291

364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.0108

AC:

1206

AN:

111955

Hom.:

Cov.:

AF XY:

0.00943

AC XY:

322

AN XY:

34153

show subpopulations

African (AFR)

AF:

0.0368

AC:

1134

AN:

30801

American (AMR)

AF:

0.00407

AC:

AN:

10576

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3527

South Asian (SAS)

AF:

0.00

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6125

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000752

AC:

AN:

53185

Other (OTH)

AF:

0.0118

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00736

Hom.:

133

Bravo

AF:

0.0130

ESP6500AA

AF:

0.0467

AC:

179

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00383

AC:

465

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

History of neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.93

CADD

Benign

9.6

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0081

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

0.23

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

REVEL

Benign

0.056

Sift

Uncertain

0.0050

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.094

MutPred

0.17

Gain of catalytic residue at M1049 (P = 0.0652)

MVP

0.093

MPC

0.12

ClinPred

0.011

GERP RS

3.8

Varity_R

0.54

gMVP

0.16

Mutation Taster

=99/1

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