NM_198536.3:c.521G>A

Variant names:

• chr19-11342864-C-T
• rs1966988827
• NM_198536.3:c.521G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198536.3(TMEM205):​c.521G>A​(p.Ser174Asn) 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. 13/21 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: 2.41
• 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]

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39395803).

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.521G>A	p.Ser174Asn	missense	Exon 3 of 3	NP_940938.1	Q6UW68
	TMEM205	NM_001145416.2		c.521G>A	p.Ser174Asn	missense	Exon 4 of 4	NP_001138888.1	Q6UW68
	TMEM205	NM_001321112.2		c.521G>A	p.Ser174Asn	missense	Exon 4 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.521G>A	p.Ser174Asn	missense	Exon 3 of 3	ENSP00000346954.4	Q6UW68
	TMEM205	ENST00000593256.6	TSL:1	c.521G>A	p.Ser174Asn	missense	Exon 4 of 4	ENSP00000468733.1	Q6UW68
	TMEM205	ENST00000447337.5	TSL:2	c.521G>A	p.Ser174Asn	missense	Exon 4 of 4	ENSP00000398258.1	Q6UW68

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Uncertain	0.54
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.17
Sift	Benign	0.070	T
Sift4G	Benign	0.15	T
Polyphen		0.28	B
Vest4		0.37
MutPred		0.54		Loss of helix (P = 0.3949)
MVP		0.17
MPC		0.25
ClinPred		0.73	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.58
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1966988827; hg19: chr19-11453540;