rs1555498821

Positions:

• chr16-3027218-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.66

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THOC6	NM_024339.5	c.748A>C	p.Thr250Pro	missense_variant	11/13	ENST00000326266.13	NP_077315.2
THOC6	NM_001347704.2	c.748A>C	p.Thr250Pro	missense_variant	12/14		NP_001334633.1
THOC6	NM_001347703.2	c.676A>C	p.Thr226Pro	missense_variant	12/14		NP_001334632.1
THOC6	NM_001142350.3	c.748A>C	p.Thr250Pro	missense_variant	11/12		NP_001135822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THOC6	ENST00000326266.13	c.748A>C	p.Thr250Pro	missense_variant	11/13	1	NM_024339.5	ENSP00000326531	P1
THOC6	ENST00000574549.5	c.676A>C	p.Thr226Pro	missense_variant	12/14	1		ENSP00000458295
THOC6	ENST00000575576.5	c.676A>C	p.Thr226Pro	missense_variant	11/13	5		ENSP00000460015
THOC6	ENST00000253952.9	c.748A>C	p.Thr250Pro	missense_variant	11/12	2		ENSP00000253952

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 07, 2020

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
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	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs1555498821; hg19: chr16-3077219;