8-55756394-T-C

Position:

• chr8-55756394-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001363177.1(TMEM68):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TMEM68 NM_001363177.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.718

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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.343A>G	p.Met115Val	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.343A>G	p.Met115Val	missense_variant	4/8	5	NM_001286657.2	ENSP00000395204.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428914 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 710008

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

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

May 16, 2024

The c.343A>G (p.M115V) alteration is located in exon 4 (coding exon 2) of the TMEM68 gene. This alteration results from a A to G substitution at nucleotide position 343, causing the methionine (M) at amino acid position 115 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	0.099
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.26	T;T;.;T;.;T;T;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.87	D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	-0.18	N;N;N;.;.;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.65	.;N;N;N;N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.43	.;T;T;T;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T;.;T;.
Polyphen		0.0010	B;B;B;.;.;.;.;.;.
Vest4		0.17
MutPred		0.35		Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);.;.;.;Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);Loss of disorder (P = 0.1303);
MVP		0.41
MPC		0.42
ClinPred		0.16	T
GERP RS		3.1
Varity_R		0.042
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-56668953;