3-3144657-A-C

Variant names:

• chr3-3144657-A-C
• rs767592189
• NM_182916.3:c.555A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_182916.3(TRNT1):​c.555A>C​(p.Gly185Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,427,044 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRNT1 NM_182916.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.272
• Publications: 2 publications found

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]

CRBN Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal recessive 2

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-3144657-A-C is Benign according to our data. Variant chr3-3144657-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2048862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.272 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNT1	NM_182916.3	c.555A>C	p.Gly185Gly	synonymous_variant	Exon 5 of 8	ENST00000251607.11	NP_886552.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRNT1	ENST00000251607.11	c.555A>C	p.Gly185Gly	synonymous_variant	Exon 5 of 8	1	NM_182916.3	ENSP00000251607.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1427044 Hom.: 0 Cov.: 29 AF XY: 0.00000422 AC XY: 3 AN XY: 710490

African (AFR) AF: 0.00 AC: 0 AN: 32480

American (AMR) AF: 0.00 AC: 0 AN: 42876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25450

East Asian (EAS) AF: 0.00 AC: 0 AN: 39008

South Asian (SAS) AF: 0.00 AC: 0 AN: 84058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52742

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1085996

Other (OTH) AF: 0.00 AC: 0 AN: 58784

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.6
DANN	Benign	0.82
PhyloP100		0.27

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

Other links and lift over

dbSNP: rs767592189; hg19: chr3-3186341;