7-130203985-T-C

Position:

• chr7-130203985-T-C

Variant summary

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

The ENST00000397622.7(TMEM209):​c.129A>G​(p.Ile43Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM209 ENST00000397622.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.554

Genes affected

TMEM209 (HGNC:21898): (transmembrane protein 209) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM209 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM209	NM_032842.4	c.129A>G	p.Ile43Met	missense_variant	2/15	ENST00000397622.7	NP_116231.2
TMEM209	NM_001363478.2	c.126A>G	p.Ile42Met	missense_variant	2/15		NP_001350407.1
TMEM209	NM_001301163.2	c.129A>G	p.Ile43Met	missense_variant	2/14		NP_001288092.1
TMEM209	NR_156699.2	n.160A>G		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM209	ENST00000397622.7	c.129A>G	p.Ile43Met	missense_variant	2/15	1	NM_032842.4	ENSP00000380747.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461284 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 28, 2024

The c.129A>G (p.I43M) alteration is located in exon 2 (coding exon 2) of the TMEM209 gene. This alteration results from a A to G substitution at nucleotide position 129, causing the isoleucine (I) at amino acid position 43 to be replaced by a methionine (M). 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	0.26
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T;.;.;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.90	N;N;N;N;D
REVEL	Benign	0.25
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;.;.
Polyphen		0.97	D;.;D;.;.
Vest4		0.91
MutPred		0.69		Loss of catalytic residue at I43 (P = 0.0028);.;Loss of catalytic residue at I43 (P = 0.0028);.;.;
MVP		0.35
MPC		0.44
ClinPred		0.92	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.85

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: rs1798321388; hg19: chr7-129843825;