X-9786562-C-T

Variant names:

• chrX-9786562-C-T
• rs933648472
• NM_001649.4:c.17C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_001649.4(SHROOM2):​c.17C>T​(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 853,901 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000040 (0 hom. 1 hem.)
• Consequence: SHROOM2 NM_001649.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.324
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09159398).
• BS2: High Hemizygotes in GnomAd4 at 2 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.17C>T	p.Pro6Leu	missense	Exon 1 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.17C>T	p.Pro6Leu	missense	Exon 1 of 10	ENSP00000370299.3	Q13796
	ENSG00000310579	ENST00000850985.1		c.17C>T	p.Pro6Leu	missense	Exon 1 of 10	ENSP00000521067.1

Frequencies

GnomAD3 genomes AF: 0.0000362 AC: 4 AN: 110356 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

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 AF: 0.00000403 AC: 3 AN: 743508 Hom.: 0 Cov.: 28 AF XY: 0.00000443 AC XY: 1 AN XY: 225692

African (AFR) AF: 0.0000662 AC: 1 AN: 15109

American (AMR) AF: 0.00 AC: 0 AN: 3920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7189

East Asian (EAS) AF: 0.00 AC: 0 AN: 11705

South Asian (SAS) AF: 0.00 AC: 0 AN: 13482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11599

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 651223

Other (OTH) AF: 0.0000722 AC: 2 AN: 27687

GnomAD4 genome AF: 0.0000453 AC: 5 AN: 110393 Hom.: 0 Cov.: 23 AF XY: 0.0000589 AC XY: 2 AN XY: 33961

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

African (AFR) AF: 0.0000969 AC: 3 AN: 30948

American (AMR) AF: 0.00 AC: 0 AN: 10661

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2602

East Asian (EAS) AF: 0.000581 AC: 2 AN: 3445

South Asian (SAS) AF: 0.00 AC: 0 AN: 2791

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 211

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52130

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 = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.0000453

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	0.32
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.32
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.011
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.25	T
Polyphen		0.012	B
Vest4		0.17
MutPred		0.21		Loss of glycosylation at P6 (P = 0.0422)
MVP		0.60
MPC		0.30
ClinPred		0.42	T
GERP RS		1.4
PromoterAI		-0.016	Neutral
Varity_R		0.21
gMVP		0.22
Mutation Taster		=98/2	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: rs933648472; hg19: chrX-9754602;