chrX-50598399-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020717.5(SHROOM4):ā€‹c.4079A>Gā€‹(p.Asn1360Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000389 in 1,208,421 control chromosomes in the GnomAD database, including 2 homozygotes. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., 2 hem., cov: 22)
Exomes š‘“: 0.000036 ( 2 hom. 11 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.26332784).
BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHROOM4NM_020717.5 linkc.4079A>G p.Asn1360Ser missense_variant Exon 8 of 9 ENST00000376020.9 NP_065768.2 Q9ULL8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHROOM4ENST00000376020.9 linkc.4079A>G p.Asn1360Ser missense_variant Exon 8 of 9 2 NM_020717.5 ENSP00000365188.2 Q9ULL8-1
SHROOM4ENST00000289292.11 linkc.4079A>G p.Asn1360Ser missense_variant Exon 8 of 10 1 ENSP00000289292.7 Q9ULL8-1
SHROOM4ENST00000460112.3 linkc.3731A>G p.Asn1244Ser missense_variant Exon 7 of 8 5 ENSP00000421450.1 Q9ULL8-2

Frequencies

GnomAD3 genomes
AF:
0.0000718
AC:
8
AN:
111399
Hom.:
0
Cov.:
22
AF XY:
0.0000595
AC XY:
2
AN XY:
33589
show subpopulations
Gnomad AFR
AF:
0.000196
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000191
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:
0.00
GnomAD3 exomes
AF:
0.0000669
AC:
12
AN:
179414
Hom.:
1
AF XY:
0.0000468
AC XY:
3
AN XY:
64092
show subpopulations
Gnomad AFR exome
AF:
0.000543
Gnomad AMR exome
AF:
0.0000737
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000376
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000356
AC:
39
AN:
1097022
Hom.:
2
Cov.:
32
AF XY:
0.0000304
AC XY:
11
AN XY:
362430
show subpopulations
Gnomad4 AFR exome
AF:
0.000758
Gnomad4 AMR exome
AF:
0.0000570
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000663
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000143
Gnomad4 OTH exome
AF:
0.0000651
GnomAD4 genome
AF:
0.0000718
AC:
8
AN:
111399
Hom.:
0
Cov.:
22
AF XY:
0.0000595
AC XY:
2
AN XY:
33589
show subpopulations
Gnomad4 AFR
AF:
0.000196
Gnomad4 AMR
AF:
0.000191
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
2
Bravo
AF:
0.000106
ESP6500AA
AF:
0.000782
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4079A>G (p.N1360S) alteration is located in exon 8 (coding exon 8) of the SHROOM4 gene. This alteration results from a A to G substitution at nucleotide position 4079, causing the asparagine (N) at amino acid position 1360 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.024
T;T;.
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.78
T;.;T
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.26
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;L;.
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-4.3
D;D;D
REVEL
Benign
0.13
Sift
Benign
0.049
D;D;D
Sift4G
Uncertain
0.039
D;D;D
Polyphen
0.71
P;P;.
Vest4
0.36
MVP
0.37
MPC
0.47
ClinPred
0.22
T
GERP RS
5.3
Varity_R
0.40
gMVP
0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145292294; hg19: chrX-50341399; API