X-50596738-T-C

Position:

• chrX-50596738-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020717.5(SHROOM4):​c.4439A>G​(p.Lys1480Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,865 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: SHROOM4 NM_020717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.308

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06845862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM4	NM_020717.5	c.4439A>G	p.Lys1480Arg	missense_variant	9/9	ENST00000376020.9	NP_065768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHROOM4	ENST00000376020.9	c.4439A>G	p.Lys1480Arg	missense_variant	9/9	2	NM_020717.5	ENSP00000365188	P1
SHROOM4	ENST00000289292.11	c.4439A>G	p.Lys1480Arg	missense_variant	9/10	1		ENSP00000289292	P1
SHROOM4	ENST00000460112.3	c.4091A>G	p.Lys1364Arg	missense_variant	8/8	5		ENSP00000421450

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097865 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363279

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

SHROOM4: PM2, BP4, BP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0075	T;T;.
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.87	D;.;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.37	N;N;.
MutationTaster	Benign	0.92	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.097
Sift	Benign	0.59	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.088
MutPred		0.41		Loss of ubiquitination at K1480 (P = 0.0059);Loss of ubiquitination at K1480 (P = 0.0059);.;
MVP		0.21
MPC		0.093
ClinPred		0.13	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.085

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: rs1929131698; hg19: chrX-50339738;