chr8-70600070-C-T

Variant names:

• chr8-70600070-C-T
• rs765404667
• NM_014294.6:c.136G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014294.6(TRAM1):​c.136G>A​(p.Ala46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A46S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRAM1 NM_014294.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13
• Publications: 1 publications found

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]

ACMG classification

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=0.12411836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6	c.136G>A	p.Ala46Thr	missense_variant	Exon 2 of 11	ENST00000262213.7	NP_055109.1
TRAM1	NM_001317804.2	c.43G>A	p.Ala15Thr	missense_variant	Exon 3 of 12		NP_001304733.1
TRAM1	NM_001317805.2	c.-123G>A		5_prime_UTR_variant	Exon 2 of 11		NP_001304734.1
TRAM1	XM_047421636.1	c.-123G>A		5_prime_UTR_variant	Exon 3 of 12		XP_047277592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM1	ENST00000262213.7	c.136G>A	p.Ala46Thr	missense_variant	Exon 2 of 11	1	NM_014294.6	ENSP00000262213.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.055	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		2.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.84	N;N
REVEL	Benign	0.024
Sift	Benign	0.45	T;T
Sift4G	Benign	0.39	T;.
Polyphen		0.0010	B;.
Vest4		0.46
MutPred		0.26		Gain of ubiquitination at K45 (P = 0.0872);.;
MVP		0.11
MPC		0.36
ClinPred		0.59	D
GERP RS		4.2
Varity_R		0.035
gMVP		0.74
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs765404667; hg19: chr8-71512305;