rs1467307417

Variant names:

• chr11-89968891-T-A
• rs1467307417
• NM_001136486.2:c.388T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001136486.2(TRIM64):​c.388T>A​(p.Trp130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRIM64 NM_001136486.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.621
• Publications: 0 publications found

Genes affected

TRIM64 (HGNC:14663): (tripartite motif containing 64) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in innate immune response; protein ubiquitination; and regulation of gene expression. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.086677134).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM64	NM_001136486.2	c.388T>A	p.Trp130Arg	missense_variant	Exon 2 of 7	ENST00000533122.4	NP_001129958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM64	ENST00000533122.4	c.388T>A	p.Trp130Arg	missense_variant	Exon 2 of 7	1	NM_001136486.2	ENSP00000483764.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 23 AN: 17350 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000660 AC: 1 AN: 15162 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00184 AC: 715 AN: 388238 Hom.: 0 Cov.: 0 AF XY: 0.00171 AC XY: 334 AN XY: 195716

⚠️ 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: 3996

American (AMR) AF: 0.000108 AC: 2 AN: 18484

Ashkenazi Jewish (ASJ) AF: 0.000150 AC: 1 AN: 6654

East Asian (EAS) AF: 0.00 AC: 0 AN: 20384

South Asian (SAS) AF: 0.00 AC: 0 AN: 29162

European-Finnish (FIN) AF: 0.00498 AC: 84 AN: 16858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1176

European-Non Finnish (NFE) AF: 0.00219 AC: 600 AN: 274140

Other (OTH) AF: 0.00161 AC: 28 AN: 17384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00133 AC: 23 AN: 17350 Hom.: 0 Cov.: 0 AF XY: 0.00150 AC XY: 13 AN XY: 8644

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

African (AFR) AF: 0.00 AC: 0 AN: 2384

American (AMR) AF: 0.00 AC: 0 AN: 2332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 524

East Asian (EAS) AF: 0.00 AC: 0 AN: 1040

South Asian (SAS) AF: 0.00 AC: 0 AN: 280

European-Finnish (FIN) AF: 0.00472 AC: 7 AN: 1482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.00178 AC: 16 AN: 8978

Other (OTH) AF: 0.00 AC: 0 AN: 212

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000506 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.388T>A (p.W130R) alteration is located in exon 1 (coding exon 1) of the TRIM64 gene. This alteration results from a T to A substitution at nucleotide position 388, causing the tryptophan (W) at amino acid position 130 to be replaced by an arginine (R). 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	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.4
DANN	Benign	0.70
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.087	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.62
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.60	T
Polyphen		0.014	B
Vest4		0.14
MVP		0.24
GERP RS		-4.0
PromoterAI		0.026	Neutral
Varity_R		0.10
gMVP		0.028

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1467307417; hg19: chr11-89702059;