8-66135006-G-T

Variant names:

• chr8-66135006-G-T
• rs61744335
• NM_184085.2:c.358G>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_184085.2(TRIM55):​c.358G>T​(p.Asp120Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000802 in 1,613,930 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (7 hom.)
• Consequence: TRIM55 NM_184085.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 5.18

Genes affected

TRIM55 (HGNC:14215): (tripartite motif containing 55) The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. This protein associates transiently with microtubules, myosin, and titin during muscle sarcomere assembly. It may act as a transient adaptor and plays a regulatory role in the assembly of sarcomeres. Four alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03018856).
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM55	NM_184085.2	c.358G>T	p.Asp120Tyr	missense_variant	Exon 3 of 10	ENST00000315962.9	NP_908973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM55	ENST00000315962.9	c.358G>T	p.Asp120Tyr	missense_variant	Exon 3 of 10	1	NM_184085.2	ENSP00000323913.4
TRIM55	ENST00000276573.11	c.358G>T	p.Asp120Tyr	missense_variant	Exon 3 of 11	1		ENSP00000276573.7
TRIM55	ENST00000353317.9	c.358G>T	p.Asp120Tyr	missense_variant	Exon 3 of 9	1		ENSP00000297348.8
TRIM55	ENST00000350034.4	c.358G>T	p.Asp120Tyr	missense_variant	Exon 3 of 5	1		ENSP00000332302.4

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000673 AC: 169 AN: 251148 Hom.: 2 AF XY: 0.000759 AC XY: 103 AN XY: 135748

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000916

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000822 AC: 1202 AN: 1461692 Hom.: 7 Cov.: 32 AF XY: 0.000875 AC XY: 636 AN XY: 727156

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00167

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000883

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74434

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.000680

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.358G>T (p.D120Y) alteration is located in exon 3 (coding exon 3) of the TRIM55 gene. This alteration results from a G to T substitution at nucleotide position 358, causing the aspartic acid (D) at amino acid position 120 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TRIM55-related disorder Benign:1

Jan 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	.;D;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.7	L;L;L;L
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.62	P;P;B;P
Vest4		0.58
MVP		0.54
MPC		0.28
ClinPred		0.15	T
GERP RS		5.5
Varity_R		0.60
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61744335; hg19: chr8-67047241; COSMIC: COSV99035533;