chrX-50695810-C-T

Variant names:

• chrX-50695810-C-T
• rs797045961
• NM_020717.5:c.245G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020717.5(SHROOM4):​c.245G>A​(p.Arg82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,210,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02
• 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):

• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21963626).
• BS2: High Hemizygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	NM_020717.5	MANE Select	c.245G>A	p.Arg82Gln	missense	Exon 2 of 9	NP_065768.2
	SHROOM4	NR_027121.3		n.421G>A		non_coding_transcript_exon	Exon 2 of 10
	SHROOM4	NR_172068.1		n.421G>A		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.245G>A	p.Arg82Gln	missense	Exon 2 of 9	ENSP00000365188.2
	SHROOM4	ENST00000289292.11	TSL:1	c.245G>A	p.Arg82Gln	missense	Exon 2 of 10	ENSP00000289292.7
	SHROOM4	ENST00000484922.1	TSL:5	n.128G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 112009 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: 0.000284

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

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1098090 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363468

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.000265 AC: 8 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842005

Other (OTH) AF: 0.00 AC: 0 AN: 46093

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 112009 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34181

African (AFR) AF: 0.00 AC: 0 AN: 30782

American (AMR) AF: 0.00 AC: 0 AN: 10610

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

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3526

South Asian (SAS) AF: 0.00 AC: 0 AN: 2604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53218

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

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	Uncertain	0.47
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.42	N
PhyloP100		3.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.33
MutPred		0.56		Loss of solvent accessibility (P = 0.0219)
MVP		0.21
MPC		0.56
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.28
gMVP		0.55
Mutation Taster		=90/10	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: rs797045961; hg19: chrX-50438810;