8-96251090-C-A

Position:

• chr8-96251090-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015942.5(MTERF3):​c.493G>T​(p.Asp165Tyr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MTERF3 NM_015942.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTERF3	NM_015942.5	c.493G>T	p.Asp165Tyr	missense_variant	4/8	ENST00000287025.4	NP_057026.3
MTERF3	NM_001286643.1	c.493G>T	p.Asp165Tyr	missense_variant	4/9		NP_001273572.1
MTERF3	XM_011517054.3	c.154G>T	p.Asp52Tyr	missense_variant	4/8		XP_011515356.1
MTERF3	NM_001362964.1	c.-78G>T		5_prime_UTR_variant	4/8		NP_001349893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTERF3	ENST00000287025.4	c.493G>T	p.Asp165Tyr	missense_variant	4/8	1	NM_015942.5	ENSP00000287025	P1
MTERF3	ENST00000523821.5	c.493G>T	p.Asp165Tyr	missense_variant	4/9	1		ENSP00000429400
MTERF3	ENST00000522822.5	c.130G>T	p.Asp44Tyr	missense_variant	2/6	2		ENSP00000430138
MTERF3	ENST00000524341.5	c.-78G>T		5_prime_UTR_variant	2/5	3		ENSP00000429267

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

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

May 25, 2022

The c.493G>T (p.D165Y) alteration is located in exon 4 (coding exon 3) of the MTERF3 gene. This alteration results from a G to T substitution at nucleotide position 493, causing the aspartic acid (D) at amino acid position 165 to be replaced by a tyrosine (Y). 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	Uncertain	0.36
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.63
MutPred		0.75		Loss of disorder (P = 0.0727);.;Loss of disorder (P = 0.0727);
MVP		0.46
MPC		0.22
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1284702355; hg19: chr8-97263318;