Genetic Variant TRAM1:p.Leu232Ile (chr8-70586947-G-T) – 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>A(p.Leu232Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,536 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: 0.0000027 ( 0 hom. )

Consequence

TRAM1
NM_014294.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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=0.27974227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6 link	c.694C>A	p.Leu232Ile	missense_variant	Exon 8 of 11	ENST00000262213.7	NP_055109.1	Q15629-1Q6FHL3
TRAM1	NM_001317804.2 link	c.601C>A	p.Leu201Ile	missense_variant	Exon 9 of 12		NP_001304733.1	Q15629-2
TRAM1	NM_001317805.2 link	c.436C>A	p.Leu146Ile	missense_variant	Exon 8 of 11		NP_001304734.1	Q15629G3XAN4
TRAM1	XM_047421636.1 link	c.436C>A	p.Leu146Ile	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>A	p.Leu232Ile	missense_variant	Exon 8 of 11	1	NM_014294.6	ENSP00000262213.2	Q15629-1
TRAM1	ENST00000521425.5 link	c.436C>A	p.Leu146Ile	missense_variant	Exon 8 of 11	2		ENSP00000428052.1	G3XAN4
TRAM1	ENST00000521049.5 link	n.732C>A		non_coding_transcript_exon_variant	Exon 6 of 7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.00000413

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:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111870

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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

Dec 09, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.694C>A (p.L232I) alteration is located in exon 8 (coding exon 8) of the TRAM1 gene. This alteration results from a C to A substitution at nucleotide position 694, causing the leucine (L) at amino acid position 232 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

0.11

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

T;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.65

.;N

PhyloP100

4.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.52

N;N

REVEL

Uncertain

0.37

Sift

Benign

0.22

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.33

.;B

Vest4

0.43

MutPred

0.49

.;Loss of stability (P = 0.1939);

MVP

0.46

MPC

0.48

ClinPred

0.62

GERP RS

5.7

Varity_R

0.11

gMVP

0.33

Mutation Taster

=55/45

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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8-70586947-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over