8-124371975-C-A

Position:

• chr8-124371975-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_194291.3(TMEM65):​c.183G>T​(p.Glu61Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.5e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM65 NM_194291.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

Genes affected

TMEM65 (HGNC:25203): (transmembrane protein 65) Predicted to be involved in cardiac ventricle development and regulation of cardiac conduction. Located in intercalated disc; mitochondrial inner membrane; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21601248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM65	NM_194291.3	c.183G>T	p.Glu61Asp	missense_variant	1/7	ENST00000297632.8	NP_919267.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM65	ENST00000297632.8	c.183G>T	p.Glu61Asp	missense_variant	1/7	1	NM_194291.3	ENSP00000297632.6
TMEM65	ENST00000704783.1	c.183G>T	p.Glu61Asp	missense_variant	1/6			ENSP00000516032.1
TMEM65	ENST00000704785.1	n.183G>T		non_coding_transcript_exon_variant	1/7			ENSP00000516033.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.46e-7 AC: 1 AN: 1341042 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 661652

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: 9.47e-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

Jul 06, 2021

The c.183G>T (p.E61D) alteration is located in exon 1 (coding exon 1) of the TMEM65 gene. This alteration results from a G to T substitution at nucleotide position 183, causing the glutamic acid (E) at amino acid position 61 to be replaced by an aspartic acid (D). 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	0.32
BayesDel_addAF	Benign	-0.0023	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Polyphen		0.99	D
Vest4		0.27
MutPred		0.10		Loss of methylation at K59 (P = 0.1);
MVP		0.093
MPC		1.5
ClinPred		0.94	D
GERP RS		1.5
Varity_R		0.14
gMVP		0.27

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: chr8-125384216;