1-201135775-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001288565.2(TMEM9):c.440G>T(p.Gly147Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM9 NM_001288565.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

Genes affected

TMEM9 (HGNC:18823): (transmembrane protein 9) Involved in intracellular pH reduction; positive regulation of canonical Wnt signaling pathway; and proton-transporting V-type ATPase complex assembly. Located in bounding membrane of organelle; intercellular bridge; and mitotic spindle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18700764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM9	NM_001288565.2	c.440G>T	p.Gly147Val	missense_variant	5/5	ENST00000367330.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM9	ENST00000367330.6	c.440G>T	p.Gly147Val	missense_variant	5/5	1	NM_001288565.2	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460344 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726498

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: 9.00e-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

Jul 11, 2023

The c.440G>T (p.G147V) alteration is located in exon 6 (coding exon 5) of the TMEM9 gene. This alteration results from a G to T substitution at nucleotide position 440, causing the glycine (G) at amino acid position 147 to be replaced by a valine (V). 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	0.081
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.028	T;T;T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.53	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.1	L;L;L;.;L
MutationTaster	Benign	0.80	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.46	N;.;N;N;.
REVEL	Benign	0.071
Sift	Benign	0.095	T;.;T;T;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.085	B;B;B;B;B
Vest4		0.44
MutPred		0.36		.;.;.;Loss of methylation at R152 (P = 0.0568);.;
MVP		0.55
MPC		0.61
ClinPred		0.29	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.45

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: rs1189415492; hg19: chr1-201104903;