SHROOM4 p.Met1049Ile

Variant names:

• chrX-50607995-C-A
• NM_020717.5:c.3147G>T
• SHROOM4 p.Met1049Ile

Your query was ambiguous. Multiple possible variants found:

• chrX-50607995-C-A
• chrX-50607995-C-G
• chrX-50607995-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020717.5(SHROOM4):​c.3147G>T​(p.Met1049Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229
• Publications: 0 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08671799).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	NM_020717.5	MANE Select	c.3147G>T	p.Met1049Ile	missense	Exon 6 of 9	NP_065768.2	Q9ULL8-1
	SHROOM4	NR_027121.3		n.3323G>T		non_coding_transcript_exon	Exon 6 of 10
	SHROOM4	NR_172068.1		n.3188G>T		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.3147G>T	p.Met1049Ile	missense	Exon 6 of 9	ENSP00000365188.2	Q9ULL8-1
	SHROOM4	ENST00000289292.11	TSL:1	c.3147G>T	p.Met1049Ile	missense	Exon 6 of 10	ENSP00000289292.7	Q9ULL8-1
	SHROOM4	ENST00000898514.1		c.3012G>T	p.Met1004Ile	missense	Exon 5 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	9.0
DANN	Benign	0.95
DEOGEN2	Benign	0.0081	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.23
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.056
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.46	T
Varity_R		0.54
gMVP		0.16
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-50350995;