rs150984011

chr3-3148141-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_182916.3(TRNT1):c.1292T>C(p.Ile431Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000565 in 1,613,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I431V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: TRNT1 NM_182916.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 6.82

Genes affected

TRNT1 (HGNC:17341): (tRNA nucleotidyl transferase 1) The protein encoded by this gene is a CCA-adding enzyme which belongs to the tRNA nucleotidyltransferase/poly(A) polymerase family. This essential enzyme functions by catalyzing the addition of the conserved nucleotide triplet CCA to the 3' terminus of tRNA molecules. Mutations in this gene result in sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

CRBN (HGNC:30185): (cereblon) This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011566609).
• BP6: Variant 3-3148141-T-C is Benign according to our data. Variant chr3-3148141-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542066.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=1, Uncertain_significance=1}. Variant chr3-3148141-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNT1	NM_182916.3	c.1292T>C	p.Ile431Thr	missense_variant	8/8	ENST00000251607.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRNT1	ENST00000251607.11	c.1292T>C	p.Ile431Thr	missense_variant	8/8	1	NM_182916.3	P1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000628 AC: 157 AN: 249816 Hom.: 0 AF XY: 0.000716 AC XY: 97 AN XY: 135456

Gnomad AFR exome AF: 0.0000642

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00548

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000751

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000562 AC: 821 AN: 1461000 Hom.: 0 Cov.: 32 AF XY: 0.000549 AC XY: 399 AN XY: 726838

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00410

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000591

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74470

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000988 Hom.: 2

Bravo AF: 0.000582

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 04-28-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.63	P;P
Vest4		0.32
MVP		0.44
MPC		0.0048
ClinPred		0.11	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.36

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: rs150984011; hg19: chr3-3189825;