Genetic Variant TRAM1:p.Leu232Phe (chr8-70586947-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014294.6(TRAM1):c.694C>T(p.Leu232Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L232I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TRAM1
NM_014294.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.77

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4184124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6 link	c.694C>T	p.Leu232Phe	missense_variant	Exon 8 of 11	ENST00000262213.7	NP_055109.1	Q15629-1Q6FHL3
TRAM1	NM_001317804.2 link	c.601C>T	p.Leu201Phe	missense_variant	Exon 9 of 12		NP_001304733.1	Q15629-2
TRAM1	NM_001317805.2 link	c.436C>T	p.Leu146Phe	missense_variant	Exon 8 of 11		NP_001304734.1	Q15629G3XAN4
TRAM1	XM_047421636.1 link	c.436C>T	p.Leu146Phe	missense_variant	Exon 9 of 12		XP_047277592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRAM1	ENST00000262213.7 link	c.694C>T	p.Leu232Phe	missense_variant	Exon 8 of 11	1	NM_014294.6	ENSP00000262213.2	Q15629-1
TRAM1	ENST00000521425.5 link	c.436C>T	p.Leu146Phe	missense_variant	Exon 8 of 11	2		ENSP00000428052.1	G3XAN4
TRAM1	ENST00000521049.5 link	n.732C>T		non_coding_transcript_exon_variant	Exon 6 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111870

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.42

T;T

MetaSVM

Uncertain

-0.017

MutationAssessor

Benign

1.8

.;L

PhyloP100

4.8

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.038

D;D

Sift4G

Benign

0.082

T;T

Polyphen

1.0

.;D

Vest4

0.51

MutPred

0.48

.;Loss of stability (P = 0.1324);

MVP

0.55

MPC

1.2

ClinPred

0.83

GERP RS

5.7

Varity_R

0.19

gMVP

0.48

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over