chrX-50596946-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020717.5(SHROOM4):ā€‹c.4231A>Cā€‹(p.Lys1411Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000703 in 1,209,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 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‘“ 0.000036 ( 0 hom., 2 hem., cov: 24)
Exomes š‘“: 0.000074 ( 0 hom. 21 hem. )

Consequence

SHROOM4
NM_020717.5 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007074088).
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.4231A>C p.Lys1411Gln missense_variant Exon 9 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.4231A>C p.Lys1411Gln missense_variant Exon 9 of 9 2 NM_020717.5 ENSP00000365188.2 Q9ULL8-1
SHROOM4ENST00000289292.11 linkc.4231A>C p.Lys1411Gln missense_variant Exon 9 of 10 1 ENSP00000289292.7 Q9ULL8-1
SHROOM4ENST00000460112.3 linkc.3883A>C p.Lys1295Gln missense_variant Exon 8 of 8 5 ENSP00000421450.1 Q9ULL8-2

Frequencies

GnomAD3 genomes
AF:
0.0000356
AC:
4
AN:
112512
Hom.:
0
Cov.:
24
AF XY:
0.0000577
AC XY:
2
AN XY:
34664
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000374
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:
0.000371
AC:
66
AN:
178054
Hom.:
0
AF XY:
0.000269
AC XY:
17
AN XY:
63214
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00239
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:
0.00
Gnomad OTH exome
AF:
0.000226
GnomAD4 exome
AF:
0.0000739
AC:
81
AN:
1096618
Hom.:
0
Cov.:
31
AF XY:
0.0000580
AC XY:
21
AN XY:
362098
show subpopulations
Gnomad4 AFR exome
AF:
0.0000379
Gnomad4 AMR exome
AF:
0.00205
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000713
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
AF:
0.0000355
AC:
4
AN:
112565
Hom.:
0
Cov.:
24
AF XY:
0.0000576
AC XY:
2
AN XY:
34727
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000374
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:
0.000138
Hom.:
0
Bravo
AF:
0.000117
ExAC
AF:
0.000338
AC:
41

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4231A>C (p.K1411Q) alteration is located in exon 9 (coding exon 9) of the SHROOM4 gene. This alteration results from a A to C substitution at nucleotide position 4231, causing the lysine (K) at amino acid position 1411 to be replaced by a glutamine (Q). 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
0.30
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.49
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0066
T;T;.
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.68
T;.;T
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.0071
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L;L;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
0.52
N;N;N
REVEL
Benign
0.18
Sift
Benign
0.12
T;T;T
Sift4G
Uncertain
0.057
T;T;T
Polyphen
0.71
P;P;.
Vest4
0.24
MVP
0.34
MPC
0.54
ClinPred
0.18
T
GERP RS
6.0
Varity_R
0.26
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs200066869; hg19: chrX-50339946; COSMIC: COSV56797476; COSMIC: COSV56797476; API