X-9894590-G-T

Variant names:

• chrX-9894590-G-T
• rs147346721
• NM_001649.4:c.682G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001649.4(SHROOM2):​c.682G>T​(p.Asp228Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,098,131 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D228N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: SHROOM2 NM_001649.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.54
• Publications: 1 publications found

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]

ENSG00000310579 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41350174).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001649.4. 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
	SHROOM2	NM_001649.4	MANE Select	c.682G>T	p.Asp228Tyr	missense	Exon 4 of 10	NP_001640.1	Q13796

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM2	ENST00000380913.8	TSL:1 MANE Select	c.682G>T	p.Asp228Tyr	missense	Exon 4 of 10	ENSP00000370299.3	Q13796
	ENSG00000310579	ENST00000850985.1		c.682G>T	p.Asp228Tyr	missense	Exon 4 of 10	ENSP00000521067.1
	ENSG00000304844	ENST00000806597.1		n.72+880C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182488 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098131 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363495

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.0000568 AC: 2 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842106

Other (OTH) AF: 0.0000217 AC: 1 AN: 46094

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.24		Loss of disorder (P = 0.0502)
MVP		0.66
MPC		0.18
ClinPred		0.81	D
GERP RS		4.4
Varity_R		0.55
gMVP		0.55
Mutation Taster		=90/10	polymorphism

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: rs147346721; hg19: chrX-9862630;