X-50598369-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020717.5(SHROOM4):​c.4109G>A​(p.Gly1370Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Consequence

SHROOM4
NM_020717.5 missense

Scores

5
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.82
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SHROOM4NM_020717.5 linkuse as main transcriptc.4109G>A p.Gly1370Glu missense_variant 8/9 ENST00000376020.9 NP_065768.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SHROOM4ENST00000376020.9 linkuse as main transcriptc.4109G>A p.Gly1370Glu missense_variant 8/92 NM_020717.5 ENSP00000365188 P1Q9ULL8-1
SHROOM4ENST00000289292.11 linkuse as main transcriptc.4109G>A p.Gly1370Glu missense_variant 8/101 ENSP00000289292 P1Q9ULL8-1
SHROOM4ENST00000460112.3 linkuse as main transcriptc.3761G>A p.Gly1254Glu missense_variant 7/85 ENSP00000421450 Q9ULL8-2

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
22

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 15, 2023The c.4109G>A (p.G1370E) alteration is located in exon 8 (coding exon 8) of the SHROOM4 gene. This alteration results from a G to A substitution at nucleotide position 4109, causing the glycine (G) at amino acid position 1370 to be replaced by a glutamic acid (E). 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
Pathogenic
0.75
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.034
T;T;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;.;D
M_CAP
Benign
0.025
D
MetaRNN
Pathogenic
0.82
D;D;D
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.1
M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-8.0
D;D;D
REVEL
Uncertain
0.43
Sift
Benign
0.035
D;D;D
Sift4G
Uncertain
0.0050
D;D;D
Polyphen
0.98
D;D;.
Vest4
0.72
MutPred
0.67
Loss of ubiquitination at K1374 (P = 0.0787);Loss of ubiquitination at K1374 (P = 0.0787);.;
MVP
0.42
MPC
0.60
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.91
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-50341369; API