chr8-70598157-C-T

Variant names:

• chr8-70598157-C-T
• rs144360822
• NM_014294.6:c.286G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_014294.6(TRAM1):​c.286G>A​(p.Val96Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,612,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TRAM1 NM_014294.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.78
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031502813).
• BP6: Variant 8-70598157-C-T is Benign according to our data. Variant chr8-70598157-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2523607.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6	c.286G>A	p.Val96Ile	missense_variant	Exon 3 of 11	ENST00000262213.7	NP_055109.1
TRAM1	NM_001317804.2	c.193G>A	p.Val65Ile	missense_variant	Exon 4 of 12		NP_001304733.1
TRAM1	NM_001317805.2	c.28G>A	p.Val10Ile	missense_variant	Exon 3 of 11		NP_001304734.1
TRAM1	XM_047421636.1	c.28G>A	p.Val10Ile	missense_variant	Exon 4 of 12		XP_047277592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM1	ENST00000262213.7	c.286G>A	p.Val96Ile	missense_variant	Exon 3 of 11	1	NM_014294.6	ENSP00000262213.2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250686 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1460462 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726546

African (AFR) AF: 0.000239 AC: 8 AN: 33426

American (AMR) AF: 0.0000449 AC: 2 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111342

Other (OTH) AF: 0.0000497 AC: 3 AN: 60314

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74288

African (AFR) AF: 0.000121 AC: 5 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.56
DEOGEN2	Benign	0.10	.;T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.61	.;N;.
PhyloP100		2.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.066
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.56	T;T;.
Polyphen		0.0	.;B;.
Vest4		0.083
MVP		0.043
MPC		0.30
ClinPred		0.024	T
GERP RS		2.9
Varity_R		0.030
gMVP		0.39
Mutation Taster		=91/9	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: rs144360822; hg19: chr8-71510392;