dbSNP rs1301481073: TMEM205:p.Arg43Leu (chr19-11345388-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198536.3(TMEM205):c.128G>T(p.Arg43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R43Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM205
NM_198536.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.24

Publications

2 publications found

Variant links:

Genes affected

TMEM205 (HGNC:29631): (transmembrane protein 205) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM205 links:

CCDC159 (HGNC:26996): (coiled-coil domain containing 159)

CCDC159 links:

RAB3D (HGNC:9779): (RAB3D, member RAS oncogene family) Enables myosin V binding activity. Involved in bone resorption and positive regulation of regulated secretory pathway. Located in cytoplasmic microtubule and secretory vesicle. [provided by Alliance of Genome Resources, Apr 2022]

RAB3D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198536.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM205	NM_198536.3	MANE Select	c.128G>T	p.Arg43Leu	missense	Exon 2 of 3	NP_940938.1	Q6UW68
TMEM205	NM_001145416.2		c.128G>T	p.Arg43Leu	missense	Exon 3 of 4	NP_001138888.1	Q6UW68
TMEM205	NM_001321112.2		c.128G>T	p.Arg43Leu	missense	Exon 3 of 4	NP_001308041.1	Q6UW68

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM205	ENST00000354882.10	TSL:1 MANE Select	c.128G>T	p.Arg43Leu	missense	Exon 2 of 3	ENSP00000346954.4	Q6UW68
TMEM205	ENST00000593256.6	TSL:1	c.128G>T	p.Arg43Leu	missense	Exon 3 of 4	ENSP00000468733.1	Q6UW68
TMEM205	ENST00000447337.5	TSL:2	c.128G>T	p.Arg43Leu	missense	Exon 3 of 4	ENSP00000398258.1	Q6UW68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251384

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0076

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.5

PhyloP100

3.2

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.59

Sift

Benign

0.17

Sift4G

Benign

0.17

Polyphen

0.88

Vest4

0.59

MutPred

0.90

Loss of MoRF binding (P = 0.1446)

MVP

0.29

MPC

0.90

ClinPred

0.98

GERP RS

5.6

PromoterAI

0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.83

Mutation Taster

=83/17

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over