X-9891044-C-A

Variant names:

• chrX-9891044-C-A
• rs899349038
• NM_001649.4:c.385C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001649.4(SHROOM2):​c.385C>A​(p.Leu129Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,201,115 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: SHROOM2 NM_001649.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.996
• Publications: 0 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: 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 (MetaRNN=0.038941503).

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.385C>A	p.Leu129Ile	missense	Exon 3 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.385C>A	p.Leu129Ile	missense	Exon 3 of 10	ENSP00000370299.3	Q13796
	ENSG00000310579	ENST00000850985.1		c.385C>A	p.Leu129Ile	missense	Exon 3 of 10	ENSP00000521067.1
	ENSG00000295228	ENST00000728736.1		n.133+20G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112462 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.00000624 AC: 1 AN: 160297 AF XY: 0.0000199

Gnomad AFR exome AF: 0.0000879

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1088653 Hom.: 0 Cov.: 29 AF XY: 0.00000281 AC XY: 1 AN XY: 355631

African (AFR) AF: 0.0000381 AC: 1 AN: 26226

American (AMR) AF: 0.00 AC: 0 AN: 34141

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19176

East Asian (EAS) AF: 0.00 AC: 0 AN: 29765

South Asian (SAS) AF: 0.00 AC: 0 AN: 52257

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837437

Other (OTH) AF: 0.00 AC: 0 AN: 45742

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112462 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34596

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000646 AC: 2 AN: 30936

American (AMR) AF: 0.00 AC: 0 AN: 10690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53243

Other (OTH) AF: 0.00 AC: 0 AN: 1517

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.31
DANN	Benign	0.86
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.021
Sift	Benign	0.048	D
Sift4G	Benign	0.16	T
Polyphen		0.20	B
Vest4		0.12
MutPred		0.10		Loss of phosphorylation at S132 (P = 0.1972)
MVP		0.26
MPC		0.080
ClinPred		0.028	T
GERP RS		-5.8
Varity_R		0.070
gMVP		0.19
Mutation Taster		=100/0	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: rs899349038; hg19: chrX-9859084;