chr1-231163501-C-A

Variant names:

• chr1-231163501-C-A
• rs773687809
• NM_001004342.5:c.532C>A

Variant summary

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

The NM_001004342.5(TRIM67):​c.532C>A​(p.Arg178Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,367,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R178L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: TRIM67 NM_001004342.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682
• Publications: 0 publications found

Genes affected

TRIM67 (HGNC:31859): (tripartite motif containing 67) Predicted to enable zinc ion binding activity. Predicted to be involved in regulation of protein localization. Predicted to act upstream of or within negative regulation of Ras protein signal transduction; positive regulation of neuron projection development; and positive regulation of ubiquitin-dependent protein catabolic process. Predicted to be located in cytoplasm and cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004342.5. 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
	TRIM67	NM_001004342.5	MANE Select	c.532C>A	p.Arg178Ser	missense	Exon 1 of 10	NP_001004342.3
	TRIM67	NM_001410937.1		c.532C>A	p.Arg178Ser	missense	Exon 1 of 10	NP_001397866.1	F8W8C1
	TRIM67	NM_001300889.3		c.412C>A	p.Arg138Ser	missense	Exon 2 of 12	NP_001287818.1	Q6ZTA4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM67	ENST00000366653.6	TSL:1 MANE Select	c.532C>A	p.Arg178Ser	missense	Exon 1 of 10	ENSP00000355613.5	Q6ZTA4-3
	TRIM67	ENST00000449018.7	TSL:1	c.412C>A	p.Arg138Ser	missense	Exon 2 of 12	ENSP00000400163.3	Q6ZTA4-2
	TRIM67	ENST00000444294.7	TSL:5	c.532C>A	p.Arg178Ser	missense	Exon 1 of 10	ENSP00000412124.3	F8W8C1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000268 AC: 3 AN: 112050 AF XY: 0.0000322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000138

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1367106 Hom.: 0 Cov.: 31 AF XY: 0.00000445 AC XY: 3 AN XY: 674542

African (AFR) AF: 0.00 AC: 0 AN: 28442

American (AMR) AF: 0.00 AC: 0 AN: 34272

Ashkenazi Jewish (ASJ) AF: 0.0000411 AC: 1 AN: 24354

East Asian (EAS) AF: 0.00 AC: 0 AN: 33382

South Asian (SAS) AF: 0.0000521 AC: 4 AN: 76778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5278

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1071670

Other (OTH) AF: 0.00 AC: 0 AN: 57108

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000201 AC: 2

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	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.055	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.68
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.040	D
Polyphen		0.96	P
Vest4		0.49
MutPred		0.56		Loss of MoRF binding (P = 0.0483)
MVP		0.66
MPC		1.6
ClinPred		0.65	D
GERP RS		4.2
Varity_R		0.53
gMVP		0.79
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs773687809; hg19: chr1-231299247;