Genetic Variant TRAM1:p.Thr137Ile (chr8-70597911-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014294.6(TRAM1):c.410C>T(p.Thr137Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,444,246 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TRAM1
NM_014294.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.86

Publications

0 publications found

Variant links:

Genes affected

TRAM1 (HGNC:20568): (translocation associated membrane protein 1) This gene encodes a multi-pass membrane protein that is part of the mammalian endoplasmic reticulum. The encoded protein influences glycosylation and facilitates the translocation of secretory proteins across the endoplasmic reticulum membrane by regulating which domains of the nascent polypeptide chain are visible to the cytosol during a translocational pause. [provided by RefSeq, Oct 2009]

TRAM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24719656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6 link	c.410C>T	p.Thr137Ile	missense_variant	Exon 4 of 11	ENST00000262213.7	NP_055109.1	Q15629-1Q6FHL3
TRAM1	NM_001317804.2 link	c.317C>T	p.Thr106Ile	missense_variant	Exon 5 of 12		NP_001304733.1	Q15629-2
TRAM1	NM_001317805.2 link	c.152C>T	p.Thr51Ile	missense_variant	Exon 4 of 11		NP_001304734.1	Q15629G3XAN4
TRAM1	XM_047421636.1 link	c.152C>T	p.Thr51Ile	missense_variant	Exon 5 of 12		XP_047277592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM1	ENST00000262213.7 link	c.410C>T	p.Thr137Ile	missense_variant	Exon 4 of 11	1	NM_014294.6	ENSP00000262213.2		Q15629-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247580

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1444246

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33164

American (AMR)

AF:

0.0000453

AC:

AN:

44136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

39130

South Asian (SAS)

AF:

0.00

AC:

AN:

82904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101686

Other (OTH)

AF:

0.00

AC:

AN:

59468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.410C>T (p.T137I) alteration is located in exon 4 (coding exon 4) of the TRAM1 gene. This alteration results from a C to T substitution at nucleotide position 410, causing the threonine (T) at amino acid position 137 to be replaced by an isoleucine (I). 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

0.10

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.20

.;T;.

Eigen

Benign

0.085

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.64

T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.2

.;L;.

PhyloP100

6.9

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.57

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.62

T;T;T

Sift4G

Benign

0.67

T;T;.

Polyphen

0.024

.;B;.

Vest4

0.82

MutPred

0.26

.;Loss of catalytic residue at T137 (P = 0.2025);.;

MVP

0.78

MPC

0.45

ClinPred

0.34

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.58

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over