8-55756360-A-G

Variant names:

• chr8-55756360-A-G
• rs1483493054
• NM_001286657.2:c.377T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001286657.2(TMEM68):​c.377T>C​(p.Ile126Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,603,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TMEM68 NM_001286657.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 1 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286657.2. 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.377T>C	p.Ile126Thr	missense	Exon 4 of 8	NP_001273586.1	Q96MH6-1
	TMEM68	NM_001363176.1		c.377T>C	p.Ile126Thr	missense	Exon 4 of 8	NP_001350105.1	Q96MH6-1
	TMEM68	NM_152417.3		c.377T>C	p.Ile126Thr	missense	Exon 4 of 6	NP_689630.1	Q96MH6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM68	ENST00000434581.7	TSL:5 MANE Select	c.377T>C	p.Ile126Thr	missense	Exon 4 of 8	ENSP00000395204.2	Q96MH6-1
	TMEM68	ENST00000617782.4	TSL:5	c.377T>C	p.Ile126Thr	missense	Exon 3 of 7	ENSP00000478242.1	Q96MH6-1
	TMEM68	ENST00000881275.1		c.377T>C	p.Ile126Thr	missense	Exon 3 of 7	ENSP00000551334.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152272 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000827 AC: 2 AN: 241792 AF XY: 0.00000766

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1451426 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 721462

African (AFR) AF: 0.0000303 AC: 1 AN: 33004

American (AMR) AF: 0.00 AC: 0 AN: 42484

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39302

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1108778

Other (OTH) AF: 0.0000167 AC: 1 AN: 60030

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74396

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000602 Hom.: 0

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.82
MutPred		0.57		Loss of stability (P = 0.0128)
MVP		0.98
MPC		0.93
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.46
gMVP		0.97
Mutation Taster		=53/47	polymorphism

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

dbSNP: rs1483493054; hg19: chr8-56668919;