chrX-50607728-T-C

Variant names:

• chrX-50607728-T-C
• rs6614552
• NM_020717.5:c.3414A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020717.5(SHROOM4):​c.3414A>G​(p.Glu1138Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,112,932 control chromosomes in the GnomAD database, including 1,063 homozygotes. There are 2,868 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1138dup) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.064 (609 hom., 1315 hem., cov: 19)
  • Exomes 𝑓: 0.0078 (454 hom. 1553 hem.)
• Consequence: SHROOM4 NM_020717.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.38
• Publications: 6 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.09).
• BP6: Variant X-50607728-T-C is Benign according to our data. Variant chrX-50607728-T-C is described in ClinVar as Benign. ClinVar VariationId is 95972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

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.3414A>G	p.Glu1138Glu	synonymous	Exon 6 of 9	NP_065768.2	Q9ULL8-1
	SHROOM4	NR_027121.3		n.3590A>G		non_coding_transcript_exon	Exon 6 of 10
	SHROOM4	NR_172068.1		n.3455A>G		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM4	ENST00000376020.9	TSL:2 MANE Select	c.3414A>G	p.Glu1138Glu	synonymous	Exon 6 of 9	ENSP00000365188.2	Q9ULL8-1
	SHROOM4	ENST00000289292.11	TSL:1	c.3414A>G	p.Glu1138Glu	synonymous	Exon 6 of 10	ENSP00000289292.7	Q9ULL8-1
	SHROOM4	ENST00000898514.1		c.3279A>G	p.Glu1093Glu	synonymous	Exon 5 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 6724 AN: 105625 Hom.: 605 Cov.: 19

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000884

Gnomad FIN AF: 0.000184

Gnomad MID AF: 0.0217

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.0494

GnomAD2 exomes AF: 0.0189 AC: 2404 AN: 127114 AF XY: 0.0125

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.000186

Gnomad FIN exome AF: 0.000829

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.00777 AC: 7827 AN: 1007271 Hom.: 454 Cov.: 27 AF XY: 0.00514 AC XY: 1553 AN XY: 302339

African (AFR) AF: 0.227 AC: 5447 AN: 23974

American (AMR) AF: 0.0126 AC: 415 AN: 32872

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 206 AN: 17629

East Asian (EAS) AF: 0.000103 AC: 3 AN: 29054

South Asian (SAS) AF: 0.00120 AC: 55 AN: 45941

European-Finnish (FIN) AF: 0.000545 AC: 21 AN: 38563

Middle Eastern (MID) AF: 0.0216 AC: 79 AN: 3663

European-Non Finnish (NFE) AF: 0.000990 AC: 765 AN: 772932

Other (OTH) AF: 0.0196 AC: 836 AN: 42643

GnomAD4 genome AF: 0.0639 AC: 6753 AN: 105661 Hom.: 609 Cov.: 19 AF XY: 0.0458 AC XY: 1315 AN XY: 28733

African (AFR) AF: 0.222 AC: 6303 AN: 28364

American (AMR) AF: 0.0263 AC: 261 AN: 9935

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 29 AN: 2565

East Asian (EAS) AF: 0.00 AC: 0 AN: 3358

South Asian (SAS) AF: 0.000887 AC: 2 AN: 2256

European-Finnish (FIN) AF: 0.000184 AC: 1 AN: 5426

Middle Eastern (MID) AF: 0.0191 AC: 4 AN: 209

European-Non Finnish (NFE) AF: 0.00163 AC: 84 AN: 51478

Other (OTH) AF: 0.0488 AC: 69 AN: 1413

Alfa AF: 0.0367 Hom.: 257

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)
-	-	1	SHROOM4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.25
DANN	Benign	0.42
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs6614552; hg19: chrX-50350728; COSMIC: COSV56788368;