7-112772849-G-A

Position:

• chr7-112772849-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022484.6(TMEM168):​c.1478C>T​(p.Pro493Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TMEM168 NM_022484.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

TMEM168 (HGNC:25826): (transmembrane protein 168) Located in transport vesicle. [provided by Alliance of Genome Resources, Apr 2022]

LINC03076 (HGNC:56656): (long intergenic non-protein coding RNA 3076)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM168	NM_022484.6	c.1478C>T	p.Pro493Leu	missense_variant	4/5	ENST00000312814.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM168	ENST00000312814.11	c.1478C>T	p.Pro493Leu	missense_variant	4/5	1	NM_022484.6	P1
LINC03076	ENST00000656697.1	n.469-123504G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 03, 2024

The c.1478C>T (p.P493L) alteration is located in exon 4 (coding exon 3) of the TMEM168 gene. This alteration results from a C to T substitution at nucleotide position 1478, causing the proline (P) at amino acid position 493 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	0.61
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.65
Sift	Benign	0.21	T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.86
MutPred		0.73		Gain of catalytic residue at P493 (P = 0.0222);Gain of catalytic residue at P493 (P = 0.0222);.;.;
MVP		0.43
MPC		0.53
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.31
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs764779279; hg19: chr7-112412904;