NM_033629.6:c.365T>C

Variant names:

• chr3-48467020-T-C
• rs79993407
• NM_033629.6:c.365T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033629.6(TREX1):​c.365T>C​(p.Val122Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TREX1 NM_033629.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.62

Genes affected

TREX1 (HGNC:12269): (three prime repair exonuclease 1) This gene encodes a nuclear protein with 3' exonuclease activity. The encoded protein may play a role in DNA repair and serve as a proofreading function for DNA polymerase. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, Cree encephalitis, and other diseases of the immune system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]

ATRIP (HGNC:33499): (ATR interacting protein) This gene encodes an essential component of the DNA damage checkpoint. The encoded protein binds to single-stranded DNA coated with replication protein A. The protein also interacts with the ataxia telangiectasia and Rad3 related protein kinase, resulting in its accumulation at intranuclear foci induced by DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

ATRIP-TREX1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREX1	NM_033629.6	c.365T>C	p.Val122Ala	missense_variant	Exon 2 of 2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3	c.*1466T>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000320211.10	NP_569055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3	c.365T>C	p.Val122Ala	missense_variant	Exon 2 of 2	6	NM_033629.6	ENSP00000486676.2
ATRIP	ENST00000320211.10	c.*1466T>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_130384.3	ENSP00000323099.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461616 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Aicardi-Goutieres syndrome 1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.56	T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0	.;D
Vest4		0.66
MVP		0.99
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.48
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs79993407; hg19: chr3-48508419;