3-63838045-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_025075.4(THOC7):c.283G>A(p.Ala95Thr) variant causes a missense change involving the alteration of a 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: 33)
• Consequence: THOC7 NM_025075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

Genes affected

THOC7 (HGNC:29874): (THO complex subunit 7) Predicted to enable RNA binding activity. Involved in mRNA export from nucleus and viral mRNA export from host cell nucleus. Located in cytosol and nuclear speck. Part of THO complex part of transcription export complex. Colocalizes with chromosome, telomeric region. [provided by Alliance of Genome Resources, Apr 2022]

C3orf49 (HGNC:25190): (chromosome 3 open reading frame 49)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THOC7	NM_025075.4	c.283G>A	p.Ala95Thr	missense_variant	4/8	ENST00000295899.10
C3orf49	NM_001355236.2	c.849+6201C>T		intron_variant		ENST00000295896.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THOC7	ENST00000295899.10	c.283G>A	p.Ala95Thr	missense_variant	4/8	1	NM_025075.4	P1
C3orf49	ENST00000295896.13	c.849+6201C>T		intron_variant		2	NM_001355236.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Nov 22, 2022

The c.283G>A (p.A95T) alteration is located in exon 4 (coding exon 4) of the THOC7 gene. This alteration results from a G to A substitution at nucleotide position 283, causing the alanine (A) at amino acid position 95 to be replaced by a threonine (T). 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	D;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.059	T;.;.
Sift4G	Uncertain	0.059	T;D;D
Polyphen		1.0	D;.;.
Vest4		0.64
MutPred		0.78		Gain of phosphorylation at A95 (P = 0.0555);.;.;
MVP		0.28
MPC		1.2
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.64
gMVP		0.58

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: chr3-63823721;