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

Variant summary

Our verdict is Benign. Variant got -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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
THOC6	NM_024339.5 link	c.40-8C>T	splice_region_variant, intron_variant	Intron 1 of 12	ENST00000326266.13	NP_077315.2	Q86W42-1
THOC6	NM_001347704.2 link	c.40-8C>T	splice_region_variant, intron_variant	Intron 2 of 13		NP_001334633.1	Q86W42-1
THOC6	NM_001347703.2 link	c.-29-12C>T	intron_variant	Intron 2 of 13		NP_001334632.1	Q86W42-2
THOC6	NM_001142350.3 link	c.40-8C>T	splice_region_variant, intron_variant	Intron 1 of 11		NP_001135822.1	Q86W42-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THOC6	ENST00000326266.13 link	c.40-8C>T		splice_region_variant, intron_variant	Intron 1 of 12	1	NM_024339.5	ENSP00000326531.8		Q86W42-1

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

GnomAD3 exomes

AF:

0.290

AC:

72712

AN:

251030

Hom.:

11178

AF XY:

0.292

AC XY:

39610

AN XY:

135642

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 SAS exome

AF:

0.241

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

Gnomad4 AFR exome

AF:

0.273

Gnomad4 AMR exome

AF:

0.209

Gnomad4 ASJ exome

AF:

0.349

Gnomad4 EAS exome

AF:

0.193

Gnomad4 SAS exome

AF:

0.249

Gnomad4 FIN exome

AF:

0.286

Gnomad4 NFE exome

AF:

0.350

Gnomad4 OTH exome

AF:

0.314

GnomAD4 genome

AF:

0.301

AC:

45731

AN:

152076

Hom.:

7217

Cov.:

AF XY:

0.294

AC XY:

21876

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.264

Gnomad4 AMR

AF:

0.267

Gnomad4 ASJ

AF:

0.365

Gnomad4 EAS

AF:

0.179

Gnomad4 SAS

AF:

0.232

Gnomad4 FIN

AF:

0.272

Gnomad4 NFE

AF:

0.345

Gnomad4 OTH

AF:

0.298

Alfa

AF:

0.326

Hom.:

5736

Bravo

AF:

0.295

Asia WGS

AF:

0.189

AC:

660

AN:

3478

EpiCase

AF:

0.349

EpiControl

AF:

0.347

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.9

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over