dbSNP rs771623038: TMEM225:p.Cys154Ser (chr11-123884077-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001013743.3(TMEM225):c.461G>C(p.Cys154Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,607,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. C154Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMEM225
NM_001013743.3 missense, splice_region

Scores

Splicing: ADA: 0.00004511

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.691

Variant links:

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]

TMEM225 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08400458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMEM225	NM_001013743.3 link	c.461G>C	p.Cys154Ser	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000375026.7	NP_001013765.2
TMEM225	NM_001363605.2 link	c.311G>C	p.Cys104Ser	missense_variant, splice_region_variant	Exon 3 of 4		NP_001350534.1
TMEM225	XM_011542802.4 link	c.328+413G>C		intron_variant	Intron 2 of 2		XP_011541104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM225	ENST00000375026.7 link	c.461G>C	p.Cys154Ser	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_001013743.3	ENSP00000364166.2		Q6GV28
TMEM225	ENST00000528595.1 link	c.311G>C	p.Cys104Ser	missense_variant, splice_region_variant	Exon 3 of 4	3		ENSP00000431282.1		E9PLT9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455610

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724094

show subpopulations

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:

0.0000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.75

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.33

.;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.084

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-4.0

D;D

REVEL

Benign

0.17

Sift

Benign

0.79

T;T

Sift4G

Benign

1.0

T;.

Vest4

0.073

MutPred

0.46

Gain of sheet (P = 0.0344);.;

MVP

0.34

MPC

0.54

ClinPred

0.24

GERP RS

2.8

gMVP

0.086

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000045

dbscSNV1_RF

Benign

0.0060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over