chr16-3027379-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_024339.5(THOC6):c.824G>T(p.Gly275Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G275D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THOC6
NM_024339.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.15

Publications

12 publications found

Variant links:

Genes affected

THOC6 (HGNC:28369): (THO complex subunit 6) This gene encodes a subunit of the multi-protein THO complex, which is involved in coordination between transcription and mRNA processing. The THO complex is a component of the TREX (transcription/export) complex, which is involved in transcription and export of mRNAs. A missense mutation in this gene is associated with a neurodevelopmental disorder called Beaulieu-Boycott-Innes syndrome. [provided by RefSeq, Dec 2016]

THOC6 Gene-Disease associations (from GenCC):

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

THOC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-3027379-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521349.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC6	NM_024339.5 link	c.824G>T	p.Gly275Val	missense_variant	Exon 12 of 13	ENST00000326266.13	NP_077315.2	Q86W42-1
THOC6	NM_001347704.2 link	c.824G>T	p.Gly275Val	missense_variant	Exon 13 of 14		NP_001334633.1	Q86W42-1
THOC6	NM_001347703.2 link	c.752G>T	p.Gly251Val	missense_variant	Exon 13 of 14		NP_001334632.1	Q86W42-2
THOC6	NM_001142350.3 link	c.810+99G>T		intron_variant	Intron 11 of 11		NP_001135822.1	Q86W42-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THOC6	ENST00000326266.13 link	c.824G>T	p.Gly275Val	missense_variant	Exon 12 of 13	1	NM_024339.5	ENSP00000326531.8	Q86W42-1
THOC6	ENST00000574549.5 link	c.752G>T	p.Gly251Val	missense_variant	Exon 13 of 14	1		ENSP00000458295.1	Q86W42-2
THOC6	ENST00000575576.5 link	c.752G>T	p.Gly251Val	missense_variant	Exon 12 of 13	5		ENSP00000460015.1	Q86W42-2
THOC6	ENST00000253952.9 link	c.810+99G>T		intron_variant	Intron 11 of 11	2		ENSP00000253952.9	Q86W42-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249820

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460488

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111422

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

D;.;D

M_CAP

Benign

0.084

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.8

M;.;.

PhyloP100

4.2

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.0

D;.;.

REVEL

Uncertain

0.50

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.96

D;.;.

Vest4

0.94

MutPred

0.72

Loss of catalytic residue at G275 (P = 0.0977);.;.;

MVP

0.66

MPC

0.55

ClinPred

0.93

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.75

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over