1-231163501-C-T

Variant names:

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

Variant summary

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

The NM_001004342.5(TRIM67):​c.532C>T​(p.Arg178Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,519,430 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TRIM67 NM_001004342.5 missense
• Clinical Significance: Not reported in ClinVar
• 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>T	p.Arg178Cys	missense	Exon 1 of 10	NP_001004342.3
	TRIM67	NM_001410937.1		c.532C>T	p.Arg178Cys	missense	Exon 1 of 10	NP_001397866.1	F8W8C1
	TRIM67	NM_001300889.3		c.412C>T	p.Arg138Cys	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>T	p.Arg178Cys	missense	Exon 1 of 10	ENSP00000355613.5	Q6ZTA4-3
	TRIM67	ENST00000449018.7	TSL:1	c.412C>T	p.Arg138Cys	missense	Exon 2 of 12	ENSP00000400163.3	Q6ZTA4-2
	TRIM67	ENST00000444294.7	TSL:5	c.532C>T	p.Arg178Cys	missense	Exon 1 of 10	ENSP00000412124.3	F8W8C1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1367106 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 674542

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24354

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 76778

European-Finnish (FIN) AF: 0.0000279 AC: 1 AN: 35822

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071670

Other (OTH) AF: 0.0000175 AC: 1 AN: 57108

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.68
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.53		Loss of MoRF binding (P = 0.0092)
MVP		0.50
MPC		1.8
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.57
gMVP		0.76
Mutation Taster		=44/56	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;