X-50596889-G-A

Variant names:

• chrX-50596889-G-A
• rs782455956
• NM_020717.5:c.4288C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_020717.5(SHROOM4):​c.4288C>T​(p.Arg1430Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,209,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000011 (0 hom. 3 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.91
• Publications: 1 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 -6 ACMG points.

• BP6: Variant X-50596889-G-A is Benign according to our data. Variant chrX-50596889-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 810600.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

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.4288C>T	p.Arg1430Cys	missense	Exon 9 of 9	NP_065768.2	Q9ULL8-1
	SHROOM4	NR_027121.3		n.4464C>T		non_coding_transcript_exon	Exon 9 of 10
	SHROOM4	NR_172068.1		n.4329C>T		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.4288C>T	p.Arg1430Cys	missense	Exon 9 of 9	ENSP00000365188.2	Q9ULL8-1
	SHROOM4	ENST00000289292.11	TSL:1	c.4288C>T	p.Arg1430Cys	missense	Exon 9 of 10	ENSP00000289292.7	Q9ULL8-1
	SHROOM4	ENST00000898514.1		c.4153C>T	p.Arg1385Cys	missense	Exon 8 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112335 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180876 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1097531 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 3 AN XY: 362915

African (AFR) AF: 0.0000379 AC: 1 AN: 26394

American (AMR) AF: 0.0000284 AC: 1 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19361

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 53925

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40458

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4116

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 841832

Other (OTH) AF: 0.00 AC: 0 AN: 46070

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112335 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34507

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30883

American (AMR) AF: 0.00 AC: 0 AN: 10674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3553

South Asian (SAS) AF: 0.00 AC: 0 AN: 2683

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53274

Other (OTH) AF: 0.00 AC: 0 AN: 1506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.9
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.77		Loss of disorder (P = 0.0249)
MVP		0.32
MPC		0.45
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.67
gMVP		0.54
Mutation Taster		=75/25	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

Other links and lift over

dbSNP: rs782455956; hg19: chrX-50339889;