X-50596789-A-G

Variant names:

• chrX-50596789-A-G
• rs1557246763
• NM_020717.5:c.4388T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020717.5(SHROOM4):​c.4388T>C​(p.Ile1463Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,098,036 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.4388T>C	p.Ile1463Thr	missense_variant	Exon 9 of 9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4388T>C	p.Ile1463Thr	missense_variant	Exon 9 of 9	2	NM_020717.5	ENSP00000365188.2
SHROOM4	ENST00000289292.11	c.4388T>C	p.Ile1463Thr	missense_variant	Exon 9 of 10	1		ENSP00000289292.7
SHROOM4	ENST00000460112.3	c.4040T>C	p.Ile1347Thr	missense_variant	Exon 8 of 8	5		ENSP00000421450.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 182988 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67474

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000527

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098036 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability, Stocco dos Santos type Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.4388T>C(p.Ile1463Thr) in SHROOM4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is reported with 0.001% allele frequency in gnomAD and is absent in 1000 Genomes. The amino acid Isoleucine at position 1463 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Ile1463Thr in SHROOM4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.61
MutPred		0.58		Gain of disorder (P = 0.0259);Gain of disorder (P = 0.0259);.;
MVP		0.34
MPC		0.59
ClinPred		0.82	D
GERP RS		4.8
Varity_R		0.58
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557246763; hg19: chrX-50339789;