NM_025075.4:c.18C>A

Variant names:

• chr3-63863773-G-T
• rs1213290117
• NM_025075.4:c.18C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025075.4(THOC7):​c.18C>A​(p.Asp6Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,100,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: THOC7 NM_025075.4 missense, splice_region
• Scores: Splicing: ADA: 0.003456
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.168
• Publications: 0 publications found

Genes affected

THOC7 (HGNC:29874): (THO complex subunit 7) Predicted to enable RNA binding activity. Involved in mRNA export from nucleus and viral mRNA export from host cell nucleus. Located in cytosol and nuclear speck. Part of THO complex part of transcription export complex. Colocalizes with chromosome, telomeric region. [provided by Alliance of Genome Resources, Apr 2022]

ATXN7 (HGNC:10560): (ataxin 7) The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the 'pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. This locus has been mapped to chromosome 3, and it has been determined that the diseased allele associated with spinocerebellar ataxia-7 contains 37-306 CAG repeats (near the N-terminus), compared to 4-35 in the normal allele. The encoded protein is a component of the SPT3/TAF9/GCN5 acetyltransferase (STAGA) and TBP-free TAF-containing (TFTC) chromatin remodeling complexes, and it thus plays a role in transcriptional regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ATXN7 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 7

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10554737).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025075.4. 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
	THOC7	NM_025075.4	MANE Select	c.18C>A	p.Asp6Glu	missense splice_region	Exon 1 of 8	NP_079351.2	Q6I9Y2
	THOC7	NM_001285387.3		c.-21C>A		splice_region	Exon 1 of 7	NP_001272316.1	A0A5S6STF9
	THOC7	NM_001285387.3		c.-21C>A		5_prime_UTR	Exon 1 of 7	NP_001272316.1	A0A5S6STF9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THOC7	ENST00000295899.10	TSL:1 MANE Select	c.18C>A	p.Asp6Glu	missense splice_region	Exon 1 of 8	ENSP00000295899.5	Q6I9Y2
	THOC7	ENST00000469584.5	TSL:2	c.-21C>A		splice_region	Exon 1 of 7	ENSP00000418518.2	A0A5S6STF9
	THOC7	ENST00000464327.2	TSL:5	c.-253C>A		splice_region	Exon 1 of 5	ENSP00000419443.2	F8WF22

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000291 AC: 32 AN: 1100596 Hom.: 0 Cov.: 30 AF XY: 0.0000322 AC XY: 17 AN XY: 527710

African (AFR) AF: 0.00 AC: 0 AN: 22840

American (AMR) AF: 0.00 AC: 0 AN: 8354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14090

East Asian (EAS) AF: 0.00 AC: 0 AN: 26714

South Asian (SAS) AF: 0.00 AC: 0 AN: 21760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2940

European-Non Finnish (NFE) AF: 0.0000341 AC: 32 AN: 938270

Other (OTH) AF: 0.00 AC: 0 AN: 44240

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.17
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.041
Sift	Benign	0.047	D
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.28		Gain of disorder (P = 0.1493)
MVP		0.12
MPC		0.44
ClinPred		0.15	T
GERP RS		1.7
PromoterAI		0.026	Neutral
Varity_R		0.18
gMVP		0.44
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.0		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: rs1213290117; hg19: chr3-63849449;