chr8-70587125-C-T

Variant names:

• chr8-70587125-C-T
• rs145890664
• NM_014294.6:c.622G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014294.6(TRAM1):​c.622G>A​(p.Ala208Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000696 in 1,613,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: TRAM1 NM_014294.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027914166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6	c.622G>A	p.Ala208Thr	missense_variant	Exon 7 of 11	ENST00000262213.7	NP_055109.1
TRAM1	NM_001317804.2	c.529G>A	p.Ala177Thr	missense_variant	Exon 8 of 12		NP_001304733.1
TRAM1	NM_001317805.2	c.364G>A	p.Ala122Thr	missense_variant	Exon 7 of 11		NP_001304734.1
TRAM1	XM_047421636.1	c.364G>A	p.Ala122Thr	missense_variant	Exon 8 of 12		XP_047277592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM1	ENST00000262213.7	c.622G>A	p.Ala208Thr	missense_variant	Exon 7 of 11	1	NM_014294.6	ENSP00000262213.2
TRAM1	ENST00000521425.5	c.364G>A	p.Ala122Thr	missense_variant	Exon 7 of 11	2		ENSP00000428052.1
TRAM1	ENST00000521049.5	n.660G>A		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000525 AC: 132 AN: 251260 AF XY: 0.000486

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000705 AC: 1030 AN: 1461666 Hom.: 1 Cov.: 31 AF XY: 0.000663 AC XY: 482 AN XY: 727120

African (AFR) AF: 0.000149 AC: 5 AN: 33464

American (AMR) AF: 0.000179 AC: 8 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000846 AC: 941 AN: 1111896

Other (OTH) AF: 0.000778 AC: 47 AN: 60392

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74486

African (AFR) AF: 0.000241 AC: 10 AN: 41562

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000657 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.622G>A (p.A208T) alteration is located in exon 7 (coding exon 7) of the TRAM1 gene. This alteration results from a G to A substitution at nucleotide position 622, causing the alanine (A) at amino acid position 208 to be replaced by a threonine (T). 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	0.081
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	.;L
PhyloP100		3.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.20
Sift	Benign	0.32	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0010	.;B
Vest4		0.47
MVP		0.62
MPC		0.37
ClinPred		0.018	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.30
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs145890664; hg19: chr8-71499360;