chr19-11345581-C-T

Variant names:

• chr19-11345581-C-T
• rs761776268
• NM_198536.3:c.39G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198536.3(TMEM205):​c.39G>A​(p.Met13Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,852 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. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM205 NM_198536.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12995708).

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.39G>A	p.Met13Ile	missense	Exon 1 of 3	NP_940938.1	Q6UW68
	TMEM205	NM_001145416.2		c.39G>A	p.Met13Ile	missense	Exon 2 of 4	NP_001138888.1	Q6UW68
	TMEM205	NM_001321112.2		c.39G>A	p.Met13Ile	missense	Exon 2 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.39G>A	p.Met13Ile	missense	Exon 1 of 3	ENSP00000346954.4	Q6UW68
	TMEM205	ENST00000593256.6	TSL:1	c.39G>A	p.Met13Ile	missense	Exon 2 of 4	ENSP00000468733.1	Q6UW68
	TMEM205	ENST00000447337.5	TSL:2	c.39G>A	p.Met13Ile	missense	Exon 2 of 4	ENSP00000398258.1	Q6UW68

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

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

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

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: 8.99e-7 AC: 1 AN: 1111988

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		1.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.094
Sift	Benign	0.30	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.38		Gain of methylation at K12 (P = 0.0439)
MVP		0.38
MPC		0.24
ClinPred		0.57	D
GERP RS		4.1
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.28
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs761776268; hg19: chr19-11456257;