19-11345356-A-G

Position:

• chr19-11345356-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198536.3(TMEM205):​c.160T>C​(p.Phe54Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,886 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: 0.0000041 (0 hom.)
• Consequence: TMEM205 NM_198536.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM205	NM_198536.3	c.160T>C	p.Phe54Leu	missense_variant	2/3	ENST00000354882.10	NP_940938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM205	ENST00000354882.10	c.160T>C	p.Phe54Leu	missense_variant	2/3	1	NM_198536.3	ENSP00000346954.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.160T>C (p.F54L) 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 160, causing the phenylalanine (F) at amino acid position 54 to be replaced by a leucine (L). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T;T;T;T;T;T;.;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	.;T;.;.;.;.;.;.;T;D;D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.1	M;M;M;M;M;M;M;M;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.0	.;D;D;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.010	.;D;D;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;D;D
Polyphen		0.47	P;P;P;P;P;P;P;P;.;.;.
Vest4		0.81
MutPred		0.82		Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);Loss of methylation at K52 (P = 0.075);
MVP		0.35
MPC		0.89
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.59
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs1217127245; hg19: chr19-11456032;