X-9891075-G-A

Position:

• chrX-9891075-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001649.4(SHROOM2):​c.416G>A​(p.Gly139Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,091,894 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: SHROOM2 NM_001649.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0840

Genes affected

SHROOM2 (HGNC:630): (shroom family member 2) This gene represents the human homolog of Xenopus laevis apical protein (APX) gene, which is implicated in amiloride-sensitive sodium channel activity. It is expressed in endothelial cells and facilitates the formation of a contractile network within endothelial cells. Depletion of this gene results in an increase in endothelial sprouting, migration, and angiogenesis. This gene is highly expressed in the retina, and is a strong candidate for ocular albinism type 1 syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04814729).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM2	NM_001649.4	c.416G>A	p.Gly139Asp	missense_variant	3/10	ENST00000380913.8	NP_001640.1
SHROOM2	XM_005274500.5	c.416G>A	p.Gly139Asp	missense_variant	3/10		XP_005274557.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHROOM2	ENST00000380913.8	c.416G>A	p.Gly139Asp	missense_variant	3/10	1	NM_001649.4	ENSP00000370299.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1091894 Hom.: 0 Cov.: 35 AF XY: 0.00000279 AC XY: 1 AN XY: 358412

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: 0.0000436

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2024

The c.416G>A (p.G139D) alteration is located in exon 3 (coding exon 3) of the SHROOM2 gene. This alteration results from a G to A substitution at nucleotide position 416, causing the glycine (G) at amino acid position 139 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.93
DEOGEN2	Benign	0.028	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.0040
Sift	Benign	0.33	T
Sift4G	Benign	0.39	T
Polyphen		0.057	B
Vest4		0.10
MutPred		0.25		Gain of solvent accessibility (P = 0.0354);
MVP		0.30
MPC		0.097
ClinPred		0.080	T
GERP RS		1.0
Varity_R		0.075
gMVP		0.32

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: rs1005093862; hg19: chrX-9859115;