11-123885346-C-A

Variant names:

• chr11-123885346-C-A
• NM_001013743.3:c.80G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001013743.3(TMEM225):​c.80G>T​(p.Gly27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM225 NM_001013743.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

Genes affected

TMEM225 (HGNC:32390): (transmembrane protein 225) Predicted to be involved in negative regulation of phosphatase activity. Predicted to be located in acrosomal membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM225	NM_001013743.3	c.80G>T	p.Gly27Val	missense_variant	Exon 1 of 4	ENST00000375026.7	NP_001013765.2
TMEM225	XM_011542802.4	c.80G>T	p.Gly27Val	missense_variant	Exon 1 of 3		XP_011541104.1
TMEM225	NM_001363605.2	c.31+49G>T		intron_variant	Intron 1 of 3		NP_001350534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM225	ENST00000375026.7	c.80G>T	p.Gly27Val	missense_variant	Exon 1 of 4	1	NM_001013743.3	ENSP00000364166.2
TMEM225	ENST00000528595.1	c.31+49G>T		intron_variant	Intron 1 of 3	3		ENSP00000431282.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.80G>T (p.G27V) alteration is located in exon 1 (coding exon 1) of the TMEM225 gene. This alteration results from a G to T substitution at nucleotide position 80, causing the glycine (G) at amino acid position 27 to be replaced by a valine (V). 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	Pathogenic	0.56
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.18	N
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.34	T
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.84
MutPred		0.36		Gain of sheet (P = 0.0061);
MVP		0.80
MPC		0.63
ClinPred		1.0	D
GERP RS		4.9
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-123756053;