rs1929137928

Variant names:

• chrX-50596867-C-T
• rs1929137928
• NM_020717.5:c.4310G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020717.5(SHROOM4):​c.4310G>A​(p.Gly1437Asp) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.264
• 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02736929).

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.4310G>A	p.Gly1437Asp	missense	Exon 9 of 9	NP_065768.2	Q9ULL8-1
	SHROOM4	NR_027121.3		n.4486G>A		non_coding_transcript_exon	Exon 9 of 10
	SHROOM4	NR_172068.1		n.4351G>A		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.4310G>A	p.Gly1437Asp	missense	Exon 9 of 9	ENSP00000365188.2	Q9ULL8-1
	SHROOM4	ENST00000289292.11	TSL:1	c.4310G>A	p.Gly1437Asp	missense	Exon 9 of 10	ENSP00000289292.7	Q9ULL8-1
	SHROOM4	ENST00000898514.1		c.4175G>A	p.Gly1392Asp	missense	Exon 8 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.75
DEOGEN2	Benign	0.0023	T
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.28	N
PhyloP100		-0.26
PrimateAI	Benign	0.38	T
PROVEAN	Benign	2.7	N
REVEL	Benign	0.036
Sift	Benign	0.36	T
Sift4G	Benign	0.73	T
Polyphen		0.0050	B
Vest4		0.11
MVP		0.16
MPC		0.15
ClinPred		0.12	T
GERP RS		2.2
Varity_R		0.089
gMVP		0.27
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1929137928; hg19: chrX-50339867; COSMIC: COSV56795393; COSMIC: COSV56795393;