Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_182916.3(TRNT1):c.810_811insAAACTT(p.Pro270_Ala271insLysLeu) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,613,238 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00067 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 4 hom. )

Consequence

TRNT1
NM_182916.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.649

Publications

3 publications found

Variant links:

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]

TRNT1 links:

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

CRBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_182916.3.

BP6

Variant 3-3147456-C-CTAAACT is Benign according to our data. Variant chr3-3147456-C-CTAAACT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00067 (102/152204) while in subpopulation EAS AF = 0.016 (83/5182). AF 95% confidence interval is 0.0132. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182916.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRNT1	NM_182916.3	MANE Select	c.810_811insAAACTT	p.Pro270_Ala271insLysLeu	conservative_inframe_insertion	Exon 7 of 8	NP_886552.3
TRNT1	NM_001367321.1		c.810_811insAAACTT	p.Pro270_Ala271insLysLeu	conservative_inframe_insertion	Exon 7 of 9	NP_001354250.1
TRNT1	NM_001367322.1		c.810_811insAAACTT	p.Pro270_Ala271insLysLeu	conservative_inframe_insertion	Exon 7 of 8	NP_001354251.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRNT1	ENST00000251607.11	TSL:1 MANE Select	c.810_811insAAACTT	p.Pro270_Ala271insLysLeu	conservative_inframe_insertion	Exon 7 of 8	ENSP00000251607.6
TRNT1	ENST00000280591.10	TSL:1	c.750_751insAAACTT	p.Pro250_Ala251insLysLeu	conservative_inframe_insertion	Exon 7 of 8	ENSP00000280591.6
TRNT1	ENST00000698413.1		c.927_928insAAACTT	p.Pro309_Ala310insLysLeu	conservative_inframe_insertion	Exon 9 of 10	ENSP00000513706.1

Frequencies

GnomAD3 genomes

AF:

0.000671

AC:

102

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00131

AC:

329

AN:

250712

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0135

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000531

AC:

776

AN:

1461034

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

420

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.0000224

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0118

AC:

469

AN:

39648

South Asian (SAS)

AF:

0.00271

AC:

234

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111512

Other (OTH)

AF:

0.00106

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152204

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0160

AC:

AN:

5182

South Asian (SAS)

AF:

0.00332

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000737

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (1)

not specified (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.65

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs527331900

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over