19-11345266-A-G

Variant names:

• chr19-11345266-A-G
• NM_198536.3:c.250T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198536.3(TMEM205):​c.250T>C​(p.Trp84Arg) 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 benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM205 NM_198536.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.694

Genes affected

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

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]

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

ACMG classification

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=0.12223911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM205	NM_198536.3	c.250T>C	p.Trp84Arg	missense_variant	Exon 2 of 3	ENST00000354882.10	NP_940938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM205	ENST00000354882.10	c.250T>C	p.Trp84Arg	missense_variant	Exon 2 of 3	1	NM_198536.3	ENSP00000346954.4

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

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.250T>C (p.W84R) alteration is located in exon 2 (coding exon 2) of the TMEM205 gene. This alteration results from a T to C substitution at nucleotide position 250, causing the tryptophan (W) at amino acid position 84 to be replaced by an arginine (R). 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	Benign	0.24
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.0064	.;T;T;T;T;T;T;T;T;T;.;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.61	T;.;T;.;.;.;.;.;.;T;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;L;L;L;L;L;L;L;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.27	.;.;N;N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.091
Sift	Benign	0.68	.;.;T;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.82	T;T;T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.12	.;B;B;B;B;B;B;B;B;.;.;.;.
Vest4		0.30
MutPred		0.51		.;Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);.;Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);Gain of methylation at W84 (P = 0.0539);
MVP		0.25
MPC		0.38
ClinPred		0.11	T
GERP RS		2.7
Varity_R		0.074
gMVP		0.69

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: chr19-11455942;