8-27287905-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_171982.5(TRIM35):​c.1127G>A​(p.Arg376His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. R376C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TRIM35
NM_171982.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.400
Variant links:
Genes affected
TRIM35 (HGNC:16285): (tripartite motif containing 35) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The function of this protein has not been identified. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16174212).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRIM35NM_171982.5 linkc.1127G>A p.Arg376His missense_variant Exon 6 of 6 ENST00000305364.9 NP_741983.2 Q9UPQ4-1
TRIM35XM_047421602.1 linkc.677G>A p.Arg226His missense_variant Exon 6 of 6 XP_047277558.1
TRIM35NM_001362813.2 linkc.*207G>A 3_prime_UTR_variant Exon 5 of 5 NP_001349742.1
TRIM35NM_001304495.2 linkc.*207G>A 3_prime_UTR_variant Exon 4 of 4 NP_001291424.1 E5RGB3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRIM35ENST00000305364.9 linkc.1127G>A p.Arg376His missense_variant Exon 6 of 6 1 NM_171982.5 ENSP00000301924.4 Q9UPQ4-1
TRIM35ENST00000521253 linkc.*207G>A 3_prime_UTR_variant Exon 4 of 4 1 ENSP00000428770.1 E5RGB3
TRIM35ENST00000521283.1 linkc.288+131G>A intron_variant Intron 4 of 4 2 ENSP00000429356.1 H0YBF3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
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
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
247604
Hom.:
0
AF XY:
0.00000743
AC XY:
1
AN XY:
134600
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000270
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1460818
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726764
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 29, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1127G>A (p.R376H) alteration is located in exon 6 (coding exon 6) of the TRIM35 gene. This alteration results from a G to A substitution at nucleotide position 1127, causing the arginine (R) at amino acid position 376 to be replaced by a histidine (H). 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
0.090
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
16
DANN
Uncertain
1.0
DEOGEN2
Benign
0.043
T
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.026
N
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.59
N
REVEL
Benign
0.097
Sift
Benign
0.092
T
Sift4G
Benign
0.085
T
Polyphen
0.62
P
Vest4
0.065
MutPred
0.67
Loss of MoRF binding (P = 0.0306);
MVP
0.49
MPC
1.1
ClinPred
0.33
T
GERP RS
2.3
Varity_R
0.028
gMVP
0.31

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs770736526; hg19: chr8-27145422; COSMIC: COSV59523314; API