16-3027379-G-A

Variant names:

• chr16-3027379-G-A
• rs200426926
• NM_024339.5:c.824G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3 PP5

The NM_024339.5(THOC6):​c.824G>A​(p.Gly275Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000364 in 1,612,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000741884: Functional expression assays demonstrated that the c.(298T>A" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: THOC6 NM_024339.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 4.15
• Publications: 12 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000741884: Functional expression assays demonstrated that the c.(298T>A; 700G>C; 824G>C) haplotype in THOC6 alters THOC6 physiological nuclear localization and its interaction with other members of the THO complex, THOC1 and THOC5 and that the pathogenicity of the haplotype results from a combined effect of at least two of the three missense changes (Mattioli, 2019).; SCV002768719: "Functional studies show that this variant causes impaired THOC1/5 interactions." PMID:30476144; SCV004175811: Functional studies show that this variant causes abnormal protein localization (Mattioli F, et. al., 2019).; SCV001759117: Functional studies of the p.[W100R; G275D; V234L] haplotype suggest a damaging effect with abnormal nuclear localization and decreased interaction with protein partners from the THO complex, and the G275D variant on its own was also suggested to decrease interaction with protein partners (Mattioli et al., 2019)
• PP5: Variant 16-3027379-G-A is Pathogenic according to our data. Variant chr16-3027379-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521349.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC6	NM_024339.5	MANE Select	c.824G>A	p.Gly275Asp	missense	Exon 12 of 13	NP_077315.2
	THOC6	NM_001347704.2		c.824G>A	p.Gly275Asp	missense	Exon 13 of 14	NP_001334633.1	Q86W42-1
	THOC6	NM_001347703.2		c.752G>A	p.Gly251Asp	missense	Exon 13 of 14	NP_001334632.1	Q86W42-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC6	ENST00000326266.13	TSL:1 MANE Select	c.824G>A	p.Gly275Asp	missense	Exon 12 of 13	ENSP00000326531.8	Q86W42-1
	THOC6	ENST00000574549.5	TSL:1	c.752G>A	p.Gly251Asp	missense	Exon 13 of 14	ENSP00000458295.1	Q86W42-2
	THOC6	ENST00000873903.1		c.842G>A	p.Gly281Asp	missense	Exon 12 of 13	ENSP00000543962.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152270 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000176 AC: 44 AN: 249820 AF XY: 0.000207

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000381 AC: 556 AN: 1460488 Hom.: 0 Cov.: 38 AF XY: 0.000358 AC XY: 260 AN XY: 726406

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86196

European-Finnish (FIN) AF: 0.000151 AC: 8 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000462 AC: 514 AN: 1111422

Other (OTH) AF: 0.000199 AC: 12 AN: 60348

GnomAD4 genome AF: 0.000203 AC: 31 AN: 152388 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74518

African (AFR) AF: 0.0000962 AC: 4 AN: 41600

American (AMR) AF: 0.0000653 AC: 1 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	-	-	THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome (6)
2	-	-	not provided (2)
-	1	-	Dystonia, early-onset, and/or spastic paraplegia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.37
Sift4G	Uncertain	0.044	D
Polyphen		0.64	P
Vest4		0.79
MVP		0.49
MPC		0.56
ClinPred		0.96	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.82
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs200426926; hg19: chr16-3077380;