NM_020717.5:c.4110G>A

Variant names:

• chrX-50598368-C-T
• rs1929223777
• NM_020717.5:c.4110G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_020717.5(SHROOM4):​c.4110G>A​(p.Gly1370Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 111,094 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. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: SHROOM4 NM_020717.5 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.76
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant X-50598368-C-T is Benign according to our data. Variant chrX-50598368-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3053385.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.

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.4110G>A	p.Gly1370Gly	synonymous	Exon 8 of 9	NP_065768.2	Q9ULL8-1
	SHROOM4	NR_027121.3		n.4286G>A		non_coding_transcript_exon	Exon 8 of 10
	SHROOM4	NR_172068.1		n.4151G>A		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.4110G>A	p.Gly1370Gly	synonymous	Exon 8 of 9	ENSP00000365188.2	Q9ULL8-1
	SHROOM4	ENST00000289292.11	TSL:1	c.4110G>A	p.Gly1370Gly	synonymous	Exon 8 of 10	ENSP00000289292.7	Q9ULL8-1
	SHROOM4	ENST00000898514.1		c.3975G>A	p.Gly1325Gly	synonymous	Exon 7 of 8	ENSP00000568573.1

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111094 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000964

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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 Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097839 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363207

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

American (AMR) AF: 0.00 AC: 0 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 54010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

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

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841935

Other (OTH) AF: 0.00 AC: 0 AN: 46085

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111094 Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1 AN XY: 33310

African (AFR) AF: 0.00 AC: 0 AN: 30533

American (AMR) AF: 0.0000964 AC: 1 AN: 10371

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2597

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53077

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SHROOM4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.5
DANN	Benign	0.64
PhyloP100		-1.8

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: rs1929223777; hg19: chrX-50341368;