8-55756394-T-C

Variant names:

• chr8-55756394-T-C
• NM_001286657.2:c.343A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting 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
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 27 codons. Genomic position: 55756316. Lost 0.125 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363177.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM68	NM_001286657.2	MANE Select	c.343A>G	p.Met115Val	missense	Exon 4 of 8	NP_001273586.1	Q96MH6-1
	TMEM68	NM_001363177.1		c.1A>G	p.Met1?	start_lost	Exon 3 of 7	NP_001350106.1
	TMEM68	NM_001286661.2		c.1A>G	p.Met1?	start_lost	Exon 2 of 5	NP_001273590.1	E5RJN2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM68	ENST00000434581.7	TSL:5 MANE Select	c.343A>G	p.Met115Val	missense	Exon 4 of 8	ENSP00000395204.2	Q96MH6-1
	TMEM68	ENST00000519780.5	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 3 of 6	ENSP00000429667.1	E5RHU1
	TMEM68	ENST00000523073.5	TSL:3	c.1A>G	p.Met1?	start_lost	Exon 2 of 5	ENSP00000429026.1	E5RJN2

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

African (AFR) AF: 0.00 AC: 0 AN: 31418

American (AMR) AF: 0.00 AC: 0 AN: 35768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25304

East Asian (EAS) AF: 0.00 AC: 0 AN: 38624

South Asian (SAS) AF: 0.00 AC: 0 AN: 78472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4942

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102272

Other (OTH) AF: 0.00 AC: 0 AN: 59064

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	-0.18	N
PhyloP100		0.72
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.29
Sift	Benign	0.43	T
Sift4G	Benign	0.58	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.35		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
Mutation Taster		=34/166	disease causing

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

Other links and lift over

hg19: chr8-56668953;