rs149300669

Variant names:

• chrX-50598534-A-G
• rs149300669
• NM_020717.5:c.3944T>C
• SHROOM4 p.Ile1315Thr

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_020717.5(SHROOM4):​c.3944T>C​(p.Ile1315Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,201,532 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 268 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., 22 hem., cov: 22)
  • Exomes 𝑓: 0.00066 (0 hom. 246 hem.)
• Consequence: SHROOM4 NM_020717.5 missense, splice_region
• Scores: Splicing: ADA: 0.003466
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 1.88
• Publications: 3 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023964018).
• BP6: Variant X-50598534-A-G is Benign according to our data. Variant chrX-50598534-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130312.
• BS2: High Hemizygotes in GnomAd4 at 22 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.3944T>C	p.Ile1315Thr	missense splice_region	Exon 8 of 9	NP_065768.2	Q9ULL8-1
	SHROOM4	NR_027121.3		n.4120T>C		splice_region non_coding_transcript_exon	Exon 8 of 10
	SHROOM4	NR_172068.1		n.3985T>C		splice_region non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.3944T>C	p.Ile1315Thr	missense splice_region	Exon 8 of 9	ENSP00000365188.2	Q9ULL8-1
	SHROOM4	ENST00000289292.11	TSL:1	c.3944T>C	p.Ile1315Thr	missense splice_region	Exon 8 of 10	ENSP00000289292.7	Q9ULL8-1
	SHROOM4	ENST00000898514.1		c.3809T>C	p.Ile1270Thr	missense splice_region	Exon 7 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes AF: 0.000679 AC: 76 AN: 111942 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000380

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000465 AC: 76 AN: 163482 AF XY: 0.000445

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000309

Gnomad ASJ exome AF: 0.000980

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000203

Gnomad NFE exome AF: 0.000736

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.000655 AC: 714 AN: 1089535 Hom.: 0 Cov.: 31 AF XY: 0.000690 AC XY: 246 AN XY: 356363

African (AFR) AF: 0.0000762 AC: 2 AN: 26243

American (AMR) AF: 0.000350 AC: 12 AN: 34279

Ashkenazi Jewish (ASJ) AF: 0.000936 AC: 18 AN: 19233

East Asian (EAS) AF: 0.00 AC: 0 AN: 29920

South Asian (SAS) AF: 0.000114 AC: 6 AN: 52474

European-Finnish (FIN) AF: 0.0000998 AC: 4 AN: 40067

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4133

European-Non Finnish (NFE) AF: 0.000765 AC: 641 AN: 837364

Other (OTH) AF: 0.000655 AC: 30 AN: 45822

GnomAD4 genome AF: 0.000679 AC: 76 AN: 111997 Hom.: 0 Cov.: 22 AF XY: 0.000644 AC XY: 22 AN XY: 34179

African (AFR) AF: 0.0000649 AC: 2 AN: 30811

American (AMR) AF: 0.000380 AC: 4 AN: 10539

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2675

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00128 AC: 68 AN: 53255

Other (OTH) AF: 0.00 AC: 0 AN: 1532

Alfa AF: 0.000856 Hom.: 34

Bravo AF: 0.000567

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	1	not specified (2)
-	1	-	Intellectual disability (1)
-	-	1	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.0036	T
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L
PhyloP100		1.9
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.12
Sift	Uncertain	0.024	D
Sift4G	Benign	0.23	T
Varity_R		0.20
gMVP		0.14
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.12
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149300669;

hg19: chrX-50341534;