16-3027170-G-A

Variant names:

• chr16-3027170-G-A
• rs150940923
• NM_024339.5:c.700G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024339.5(THOC6):​c.700G>A​(p.Val234Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V234L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: THOC6 NM_024339.5 missense, splice_region
• Scores: Splicing: ADA: 0.5516
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70
• Publications: 8 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: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29686671).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC6	NM_024339.5	MANE Select	c.700G>A	p.Val234Ile	missense splice_region	Exon 11 of 13	NP_077315.2
	THOC6	NM_001347704.2		c.700G>A	p.Val234Ile	missense splice_region	Exon 12 of 14	NP_001334633.1
	THOC6	NM_001347703.2		c.628G>A	p.Val210Ile	missense splice_region	Exon 12 of 14	NP_001334632.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC6	ENST00000326266.13	TSL:1 MANE Select	c.700G>A	p.Val234Ile	missense splice_region	Exon 11 of 13	ENSP00000326531.8
	THOC6	ENST00000574549.5	TSL:1	c.628G>A	p.Val210Ile	missense splice_region	Exon 12 of 14	ENSP00000458295.1
	THOC6	ENST00000575576.5	TSL:5	c.628G>A	p.Val210Ile	missense splice_region	Exon 11 of 13	ENSP00000460015.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.099
Sift4G	Benign	0.23	T
Polyphen		0.69	P
Vest4		0.36
MutPred		0.37		Loss of sheet (P = 0.1501)
MVP		0.36
MPC		0.085
ClinPred		0.46	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.20
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.55
dbscSNV1_RF	Benign	0.53
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: rs150940923; hg19: chr16-3077171;