Genetic Variant NM_015942.5:c.643A>G (chr8-96250940-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_015942.5(MTERF3):c.643A>G(p.Ile215Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,609,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MTERF3
NM_015942.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

MTERF3 (HGNC:24258): (mitochondrial transcription termination factor 3) Enables transcription cis-regulatory region binding activity. Involved in negative regulation of transcription, DNA-templated. Located in cytosol and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

MTERF3 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=0.24802926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTERF3	NM_015942.5 link	c.643A>G	p.Ile215Val	missense_variant	Exon 4 of 8	ENST00000287025.4	NP_057026.3	Q96E29-1
MTERF3	NM_001286643.1 link	c.643A>G	p.Ile215Val	missense_variant	Exon 4 of 9		NP_001273572.1	E5RIK9
MTERF3	NM_001362964.1 link	c.73A>G	p.Ile25Val	missense_variant	Exon 4 of 8		NP_001349893.1
MTERF3	XM_011517054.3 link	c.304A>G	p.Ile102Val	missense_variant	Exon 4 of 8		XP_011515356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MTERF3	ENST00000287025.4 link	c.643A>G	p.Ile215Val	missense_variant	Exon 4 of 8	1	NM_015942.5	ENSP00000287025.3	Q96E29-1
MTERF3	ENST00000523821.5 link	c.643A>G	p.Ile215Val	missense_variant	Exon 4 of 9	1		ENSP00000429400.1	E5RIK9
MTERF3	ENST00000522822.5 link	c.280A>G	p.Ile94Val	missense_variant	Exon 2 of 6	2		ENSP00000430138.1	Q96E29-3
MTERF3	ENST00000524341.5 link	c.73A>G	p.Ile25Val	missense_variant	Exon 2 of 5	3		ENSP00000429267.1	E5RIY4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000243

AC:

AN:

246528

Hom.:

AF XY:

0.0000300

AC XY:

AN XY:

133256

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000554

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1457248

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724800

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.643A>G (p.I215V) alteration is located in exon 4 (coding exon 3) of the MTERF3 gene. This alteration results from a A to G substitution at nucleotide position 643, causing the isoleucine (I) at amino acid position 215 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

0.083

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;.;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.70

T;T;T;T

M_CAP

Benign

0.0080

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.85

N;N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.012

D;T;T;T

Sift4G

Uncertain

0.028

D;D;T;D

Polyphen

0.97

D;.;.;D

Vest4

0.37

MutPred

0.55

Loss of catalytic residue at L220 (P = 0.061);.;.;Loss of catalytic residue at L220 (P = 0.061);

MVP

0.29

MPC

0.034

ClinPred

0.16

GERP RS

3.6

Varity_R

0.082

gMVP

0.36

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