8-55756364-G-C

Position:

• chr8-55756364-G-C

Variant summary

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

The NM_001286657.2(TMEM68):​c.373C>G​(p.Leu125Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM68 NM_001286657.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57

Genes affected

TMEM68 (HGNC:26510): (transmembrane protein 68) Predicted to enable acyltransferase activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM68 (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
TMEM68	NM_001286657.2	c.373C>G	p.Leu125Val	missense_variant	4/8	ENST00000434581.7	NP_001273586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM68	ENST00000434581.7	c.373C>G	p.Leu125Val	missense_variant	4/8	5	NM_001286657.2	ENSP00000395204.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000422 AC: 1 AN: 236998 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Nov 03, 2022

The c.373C>G (p.L125V) alteration is located in exon 4 (coding exon 2) of the TMEM68 gene. This alteration results from a C to G substitution at nucleotide position 373, causing the leucine (L) at amino acid position 125 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	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;.;D;.;T;D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D;D;T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.2	M;M;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	.;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.030	.;D;D;T;T;T;D;D;D
Sift4G	Benign	0.097	T;T;T;T;T;T;.;D;.
Polyphen		0.95	P;P;P;.;.;.;.;.;.
Vest4		0.73
MutPred		0.41		Loss of stability (P = 0.1976);Loss of stability (P = 0.1976);Loss of stability (P = 0.1976);.;.;.;Loss of stability (P = 0.1976);Loss of stability (P = 0.1976);Loss of stability (P = 0.1976);
MVP		0.94
MPC		1.2
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.26
gMVP		0.90

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: rs1207697187; hg19: chr8-56668923;