Variant 8-142735367-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016647.3(THEM6):c.555C>G(p.Ile185Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,578,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

THEM6
NM_016647.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.297

Variant links:

Genes affected

THEM6 (HGNC:29656): (thioesterase superfamily member 6) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

THEM6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.0738343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
THEM6	NM_016647.3 linkuse as main transcript	c.555C>G	p.Ile185Met	missense_variant	2/2	ENST00000336138.4	NP_057731.1
THEM6	NM_001363000.2 linkuse as main transcript	c.396C>G	p.Ile132Met	missense_variant	2/2		NP_001349929.1
THEM6	NR_156431.2 linkuse as main transcript	n.1209C>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
THEM6	ENST00000336138.4 linkuse as main transcript	c.555C>G	p.Ile185Met	missense_variant	2/2	1	NM_016647.3	ENSP00000338607	P1
THEM6	ENST00000518798.1 linkuse as main transcript	n.838C>G		non_coding_transcript_exon_variant	1/2	2
THEM6	ENST00000520217.1 linkuse as main transcript	c.180C>G	p.Ile60Met	missense_variant, NMD_transcript_variant	2/3	3		ENSP00000427970

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000511

AC:

AN:

195790

Hom.:

AF XY:

0.00000952

AC XY:

AN XY:

105068

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000343

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1425888

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705910

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000251

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.555C>G (p.I185M) alteration is located in exon 2 (coding exon 2) of the THEM6 gene. This alteration results from a C to G substitution at nucleotide position 555, causing the isoleucine (I) at amino acid position 185 to be replaced by a methionine (M). 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

0.20

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

6.6

DANN

Uncertain

0.98

DEOGEN2

Benign

0.022

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.69

M_CAP

Benign

0.021

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.87

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.97

REVEL

Benign

0.054

Sift

Benign

0.14

Sift4G

Benign

0.098

Polyphen

0.16

Vest4

0.10

MutPred

0.59

Gain of disorder (P = 0.0099);

MVP

0.23

MPC

1.2

ClinPred

0.38

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over