19-11345388-C-T

Variant names:

• chr19-11345388-C-T
• rs1301481073
• NM_198536.3:c.128G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198536.3(TMEM205):​c.128G>A​(p.Arg43Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TMEM205 NM_198536.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 2 publications found

Genes affected

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

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

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM205	NM_198536.3	MANE Select	c.128G>A	p.Arg43Gln	missense	Exon 2 of 3	NP_940938.1	Q6UW68
	TMEM205	NM_001145416.2		c.128G>A	p.Arg43Gln	missense	Exon 3 of 4	NP_001138888.1	Q6UW68
	TMEM205	NM_001321112.2		c.128G>A	p.Arg43Gln	missense	Exon 3 of 4	NP_001308041.1	Q6UW68

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM205	ENST00000354882.10	TSL:1 MANE Select	c.128G>A	p.Arg43Gln	missense	Exon 2 of 3	ENSP00000346954.4	Q6UW68
	TMEM205	ENST00000593256.6	TSL:1	c.128G>A	p.Arg43Gln	missense	Exon 3 of 4	ENSP00000468733.1	Q6UW68
	TMEM205	ENST00000447337.5	TSL:2	c.128G>A	p.Arg43Gln	missense	Exon 3 of 4	ENSP00000398258.1	Q6UW68

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251384 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.26
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.87		Loss of methylation at R39 (P = 0.1374)
MVP		0.29
MPC		0.88
ClinPred		0.97	D
GERP RS		5.6
PromoterAI		0.0060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.71
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1301481073; hg19: chr19-11456064; COSMIC: COSV61514607; COSMIC: COSV61514607;