1-111486604-C-G

Variant names:

• chr1-111486604-C-G
• rs144531991
• NM_020683.7:c.854G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020683.7(TMIGD3):​c.854G>C​(p.Arg285Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: TMIGD3 NM_020683.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0920

Genes affected

TMIGD3 (HGNC:51375): (transmembrane and immunoglobulin domain containing 3) This gene encodes a transmembrane and immunoglobulin domain-containing protein. Alternative splicing results in multiple transcript variants, one of which shares its 5' terminal exon with that of the overlapping adenosine A3 receptor gene (GeneID:140), thus resulting in a fusion product. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11176211).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIGD3	NM_020683.7	c.854G>C	p.Arg285Pro	missense_variant	Exon 4 of 6	ENST00000369716.9	NP_065734.5
TMIGD3	NM_001081976.3	c.611G>C	p.Arg204Pro	missense_variant	Exon 4 of 6		NP_001075445.1
TMIGD3	NM_001302680.2	c.347G>C	p.Arg116Pro	missense_variant	Exon 3 of 5		NP_001289609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMIGD3	ENST00000369716.9	c.854G>C	p.Arg285Pro	missense_variant	Exon 4 of 6	1	NM_020683.7	ENSP00000358730.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.854G>C (p.R285P) alteration is located in exon 4 (coding exon 4) of the ADORA3 gene. This alteration results from a G to C substitution at nucleotide position 854, causing the arginine (R) at amino acid position 285 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.1
DANN	Benign	0.65
DEOGEN2	Benign	0.027	.;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.55	T;T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.49	N;N;D;.
REVEL	Benign	0.18
Sift	Uncertain	0.019	D;D;T;.
Sift4G	Benign	0.088	T;T;T;T
Vest4		0.16
MutPred		0.62		Loss of MoRF binding (P = 6e-04);.;.;.;
MVP		0.061
MPC		0.039
ClinPred		0.13	T
GERP RS		-1.9
Varity_R		0.14
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs144531991; hg19: chr1-112029226;