1-231163717-C-A

Variant names:

• chr1-231163717-C-A
• rs947881576
• NM_001004342.5:c.748C>A

Variant summary

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

The NM_001004342.5(TRIM67):​c.748C>A​(p.Leu250Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRIM67 NM_001004342.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.695

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM67	NM_001004342.5	c.748C>A	p.Leu250Met	missense_variant	Exon 1 of 10	ENST00000366653.6	NP_001004342.3
TRIM67	NM_001410937.1	c.748C>A	p.Leu250Met	missense_variant	Exon 1 of 10		NP_001397866.1
TRIM67	NM_001300889.3	c.628C>A	p.Leu210Met	missense_variant, splice_region_variant	Exon 2 of 12		NP_001287818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM67	ENST00000366653.6	c.748C>A	p.Leu250Met	missense_variant	Exon 1 of 10	1	NM_001004342.5	ENSP00000355613.5
TRIM67	ENST00000449018.7	c.628C>A	p.Leu210Met	missense_variant, splice_region_variant	Exon 2 of 12	1		ENSP00000400163.3
TRIM67	ENST00000444294.7	c.748C>A	p.Leu250Met	missense_variant	Exon 1 of 10	5		ENSP00000412124.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1350324 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 665732

Gnomad4 AFR exome AF: 0.00

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.748C>A (p.L250M) alteration is located in exon 1 (coding exon 1) of the TRIM67 gene. This alteration results from a C to A substitution at nucleotide position 748, causing the leucine (L) at amino acid position 250 to be replaced by a methionine (M). 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	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.81	.;.;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.35
MutPred		0.24		Gain of methylation at K247 (P = 0.0872);.;Gain of methylation at K247 (P = 0.0872);
MVP		0.76
MPC		1.5
ClinPred		0.82	D
GERP RS		2.4
Varity_R		0.50
gMVP		0.43

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: rs947881576; hg19: chr1-231299463;