8-70586905-A-G

Variant names:

• chr8-70586905-A-G
• NM_014294.6:c.736T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014294.6(TRAM1):​c.736T>C​(p.Tyr246His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TRAM1 NM_014294.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28398928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM1	NM_014294.6	c.736T>C	p.Tyr246His	missense_variant	Exon 8 of 11	ENST00000262213.7	NP_055109.1
TRAM1	NM_001317804.2	c.643T>C	p.Tyr215His	missense_variant	Exon 9 of 12		NP_001304733.1
TRAM1	NM_001317805.2	c.478T>C	p.Tyr160His	missense_variant	Exon 8 of 11		NP_001304734.1
TRAM1	XM_047421636.1	c.478T>C	p.Tyr160His	missense_variant	Exon 9 of 12		XP_047277592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM1	ENST00000262213.7	c.736T>C	p.Tyr246His	missense_variant	Exon 8 of 11	1	NM_014294.6	ENSP00000262213.2
TRAM1	ENST00000521425.5	c.478T>C	p.Tyr160His	missense_variant	Exon 8 of 11	2		ENSP00000428052.1
TRAM1	ENST00000521049.5	n.774T>C		non_coding_transcript_exon_variant	Exon 6 of 7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.736T>C (p.Y246H) alteration is located in exon 8 (coding exon 8) of the TRAM1 gene. This alteration results from a T to C substitution at nucleotide position 736, causing the tyrosine (Y) at amino acid position 246 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	1.0	.;L
PhyloP100		5.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.15	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.51	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.98	.;D
Vest4		0.36
MutPred		0.45		.;Gain of disorder (P = 0.0185);
MVP		0.60
MPC		1.3
ClinPred		0.85	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.70
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr8-71499140;