16-3027218-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024339.5(THOC6):c.748A>C(p.Thr250Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THOC6
NM_024339.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.66

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THOC6	NM_024339.5 link	c.748A>C	p.Thr250Pro	missense_variant	Exon 11 of 13	ENST00000326266.13	NP_077315.2	Q86W42-1
THOC6	NM_001347704.2 link	c.748A>C	p.Thr250Pro	missense_variant	Exon 12 of 14		NP_001334633.1	Q86W42-1
THOC6	NM_001347703.2 link	c.676A>C	p.Thr226Pro	missense_variant	Exon 12 of 14		NP_001334632.1	Q86W42-2
THOC6	NM_001142350.3 link	c.748A>C	p.Thr250Pro	missense_variant	Exon 11 of 12		NP_001135822.1	Q86W42-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THOC6	ENST00000326266.13 link	c.748A>C	p.Thr250Pro	missense_variant	Exon 11 of 13	1	NM_024339.5	ENSP00000326531.8	Q86W42-1
THOC6	ENST00000574549.5 link	c.676A>C	p.Thr226Pro	missense_variant	Exon 12 of 14	1		ENSP00000458295.1	Q86W42-2
THOC6	ENST00000575576.5 link	c.676A>C	p.Thr226Pro	missense_variant	Exon 11 of 13	5		ENSP00000460015.1	Q86W42-2
THOC6	ENST00000253952.9 link	c.748A>C	p.Thr250Pro	missense_variant	Exon 11 of 12	2		ENSP00000253952.9	Q86W42-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome

Pathogenic:1

Nov 07, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Uncertain:1

Jan 09, 2015

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.072

T;.;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

D;.;D;D

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;.;L

PhyloP100

4.7

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.3

N;.;.;N

REVEL

Benign

0.17

Sift4G

Uncertain

0.046

D;T;T;T

Polyphen

0.99

D;.;.;D

Vest4

0.69

MutPred

0.40

Gain of glycosylation at T250 (P = 0.0352);.;.;Gain of glycosylation at T250 (P = 0.0352);

MVP

0.56

MPC

0.53

ClinPred

0.89

GERP RS

5.2

Varity_R

0.96

gMVP

0.46

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over