Genetic Variant THOC6:c.40-8C>T (chr16-3025700-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024339.5(THOC6):c.40-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,612,008 control chromosomes in the GnomAD database, including 88,565 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7217 hom., cov: 33)

Exomes 𝑓: 0.33 ( 81348 hom. )

Consequence

THOC6
NM_024339.5 splice_region, intron

Scores

Splicing: ADA: 0.0001452

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.262

Publications

8 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: Ambry Genetics, G2P, Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

THOC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 16-3025700-C-T is Benign according to our data. Variant chr16-3025700-C-T is described in ClinVar as Benign. ClinVar VariationId is 1342292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024339.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
THOC6	NM_024339.5	MANE Select	c.40-8C>T	splice_region intron	N/A	NP_077315.2
THOC6	NM_001347704.2		c.40-8C>T	splice_region intron	N/A	NP_001334633.1	Q86W42-1
THOC6	NM_001347703.2		c.-29-12C>T	intron	N/A	NP_001334632.1	Q86W42-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
THOC6	ENST00000326266.13	TSL:1 MANE Select	c.40-8C>T	splice_region intron	N/A	ENSP00000326531.8	Q86W42-1
THOC6	ENST00000574549.5	TSL:1	c.-29-12C>T	intron	N/A	ENSP00000458295.1	Q86W42-2
THOC6	ENST00000571057.5	TSL:1	n.324-8C>T	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.301

AC:

45705

AN:

151958

Hom.:

7210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.264

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.267

Gnomad ASJ

AF:

0.365

Gnomad EAS

AF:

0.178

Gnomad SAS

AF:

0.232

Gnomad FIN

AF:

0.272

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.345

Gnomad OTH

AF:

0.302

GnomAD2 exomes

AF:

0.290

AC:

72712

AN:

251030

AF XY:

0.292

show subpopulations

Gnomad AFR exome

AF:

0.268

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.349

Gnomad EAS exome

AF:

0.178

Gnomad FIN exome

AF:

0.283

Gnomad NFE exome

AF:

0.346

Gnomad OTH exome

AF:

0.301

GnomAD4 exome

AF:

0.330

AC:

481088

AN:

1459932

Hom.:

81348

Cov.:

AF XY:

0.328

AC XY:

238256

AN XY:

726352

show subpopulations

African (AFR)

AF:

0.273

AC:

9120

AN:

33430

American (AMR)

AF:

0.209

AC:

9360

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.349

AC:

9117

AN:

26124

East Asian (EAS)

AF:

0.193

AC:

7675

AN:

39680

South Asian (SAS)

AF:

0.249

AC:

21467

AN:

86212

European-Finnish (FIN)

AF:

0.286

AC:

15290

AN:

53410

Middle Eastern (MID)

AF:

0.329

AC:

1893

AN:

5760

European-Non Finnish (NFE)

AF:

0.350

AC:

388203

AN:

1110304

Other (OTH)

AF:

0.314

AC:

18963

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

17726

35452

53178

70904

88630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12188

24376

36564

48752

60940

<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

AF:

0.301

AC:

45731

AN:

152076

Hom.:

7217

Cov.:

AF XY:

0.294

AC XY:

21876

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.264

AC:

10940

AN:

41496

American (AMR)

AF:

0.267

AC:

4084

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.365

AC:

1265

AN:

3468

East Asian (EAS)

AF:

0.179

AC:

922

AN:

5162

South Asian (SAS)

AF:

0.232

AC:

1120

AN:

4818

European-Finnish (FIN)

AF:

0.272

AC:

2878

AN:

10570

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.345

AC:

23460

AN:

67978

Other (OTH)

AF:

0.298

AC:

628

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1677

3354

5032

6709

8386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.325

Hom.:

6379

Bravo

AF:

0.295

Asia WGS

AF:

0.189

AC:

660

AN:

3478

EpiCase

AF:

0.349

EpiControl

AF:

0.347

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.9

(source)

DANN

Benign

0.60

PhyloP100

-0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.018

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over